Adenosine analogs for treatment of disease

Abstract

The present disclosure provides adenosine analogs useful in the treatment of diseases such as pain and inflammatory conditions.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 376,371 filed on September 20, 2022 and U.S. Provisional Patent Application No. 63 / 434,229 filed on December 21, 2022, the entire contents of each of which are incorporated herein by reference. Background Art

[0003] When cells are stressed or damaged, or when neurotransmitters are released from neurons, the extracellular concentration of adenosine, a purine nucleoside, increases dramatically. This occurs in most, if not all, organs, including the nervous system. The cellular response to adenosine is expressed by the molecules designated A1, A2, and A3. 2A , A 2B Adenosine receptors are mediated by four G protein-coupled receptors, A1, A2, and A3. These adenosine receptor subtypes are found on many different cell types in most, if not all, tissues, and in at least some cases, their expression is known to increase in the presence of pathology or disease. Although adenosine activates all four receptor subtypes, various compounds and drugs have varying abilities to modulate one subtype over the others. Therapeutically, the use of selective adenosine receptor modulators may have the advantage of avoiding potential deleterious effects due to the involvement of one or more other subtypes.

[0004] Acting through adenosine receptors, increased extracellular adenosine concentrations can regulate responses from the innate immune system, the inappropriate activation of which has been implicated in many diseases and conditions. Adenosine receptor activation can also change the properties of astrocytes, microglia, and neurons in the nervous system. Via a mechanism, activation of A3 adenosine receptors (A3AR) can inhibit the formation of NLRP3 (NOD-like receptor family pyrin domain-containing protein 3) inflammasomes, which are intracellular multiprotein complexes that lead to the generation of interleukin-1β (IL-1β). IL-1β is a key mediator of acute and chronic inflammatory responses. Activating A3AR with agonists and partial agonists has been shown to inhibit inflammasome activity, and thereby reduce inflammation and pain caused by IL-1β and other proinflammatory cytokines. In addition, chronic inflammation mediated by inflammasomes is often associated with cell degeneration (e.g., central nervous system cell loss in neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease).

[0005] Chronic inflammatory diseases affecting various tissue types are also known to involve dysfunction of the mitochondria of cells, which provide the energy required to drive all cellular processes. Insufficient energy enhances cellular stress and, when severe, leads to cell degeneration. Mitochondrial dysfunction can lead to inflammation, and inflammation can lead to mitochondrial dysfunction. A3 adenosine receptor (AR) agonists are known to prevent mitochondrial damage and inhibit cell degeneration.

[0006] Activation of A3AR is known to promote multiple cell signaling pathways. A3AR inhibits adenylate cyclase activity through the Gi G protein and stimulates the phospholipase C / inositol trisphosphate / diacylglycerol pathway via the Gβγ G protein. These receptors are also coupled to mitogen-activated protein kinases (MAPKs), including ERK 1 and ERK 2. The Gβγ protein also mediates the regulation of voltage-gated calcium channels and G protein-gated inwardly rectifying potassium channels (GIRK and Kir6) to inhibit hyperexcitability. In addition, activation of A3AR is coupled to the translocation of β-arrestin. Previous studies have shown that some A3AR agonists with a bridge methanocarba (bicyclo[3.1.0]hexyl) motif instead of a ribose ring exhibit biased agonism, which means that the compound shows different potencies and efficacies for the pathways triggered by ligand binding (Baltos et al., Mol. Pharmacol. 90:12 (2016)). The utility and safety of A3AR agonists depend on the activity profile and profile required for anti-inflammatory or analgesic activity. Previous studies with structurally dissimilar A3AR agonists cannot predict the activity profile of the novel compounds described in this application.

[0007] Tissue inflammation is often accompanied by pain. Pain attributed to damage to certain regions of the peripheral nerves as well as the central nervous system is called neuropathic pain. Multiple lines of evidence indicate that some chronic inflammatory pain conditions, including but not limited to chronic neuropathic pain and chronic mixed pain conditions that combine both common inflammatory pain and neuropathic pain, involve inflammasome activity. Selective A3AR agonists are analgesics for chronic inflammatory pain, neuropathic pain, and mixed pain conditions. A3AR-mediated analgesia is accompanied by mitochondrial protection and a decrease in the levels of IL-1β and other pro-inflammatory cytokines.

[0008] In the central nervous system, chronic inflammasome activity that leads to increased levels of IL-1β and other proinflammatory cytokines induces widespread cognitive impairment. For example, patients exposed to certain chemotherapeutic drugs show a persistent (several months to years) condition known as chemotherapy-induced cognitive impairment ("chemo-brain"; "chemo-fog"). Patients recovering from head trauma show a similar syndrome (traumatic brain injury-induced cognitive dysfunction or "post-concussion syndrome"). Cognitive impairment syndrome is also seen after surgery, especially after cardiopulmonary bypass surgery and especially in the elderly (postoperative cognitive dysfunction). Infection with COVID-19 often leads to cognitive impairment (Nasserie et al., 2021) and increases the reactivity of microglia (Fernandez-Castaneda et al., 2022). Microglia express A3 adenosine receptors at very high levels, so that A3AR agonists may be particularly effective in these cells. The activation of microglia then causes the formation of neurotoxic astrocytes. A3AR agonists can reduce cognitive impairment by reducing inflammation involving microglia and astrocytes. Cognitive impairment can also result from tumors in the CNS such as glioblastoma, and A3AR agonists can prevent such impairment. Selective A3AR agonists can treat and prevent cognitive impairment syndromes.

[0009] The innate immune system responds to a variety of toxins including certain plant alkaloids such as morphine and its synthetic homologues (collectively referred to as opioids). Exposure to analgesic levels of opioids results in inflammasome formation, increased levels of IL-1β, and a pro-inflammatory cascade that promotes many of the undesirable side effects of opioids, including but not limited to physiological dependence (a contributing factor to addiction) and analgesic tolerance (a phenomenon in which repeated doses of opioids produce diminishing analgesia, thus requiring escalating doses to maintain adequate analgesia). Selective A3AR agonists can attenuate opioid-induced inflammasome activation, dependence / addiction, and tolerance.

[0010] Inhibiting voltage-gated calcium channels in nociceptors is a clinically proven means of treating neuropathic pain, as demonstrated by clinical studies with gabapentin and the peptide Prialt. Activation of adenosine receptors in nociceptors inhibits the activation of CaV2.1 and CaV2.2 channels, thereby mimicking the action of direct inhibitors of said channels and thus suppressing painful nociception. In some studies, the effect of adenosine on voltage-gated calcium channels can be recapitulated by selective activation of A3AR, indicating the importance of this pathway for analgesic activity. In some cases, activation of A3AR also leads to activation of inwardly rectifying potassium channels, particularly Kir3 and Kir6 channels, and this activation can inhibit hyperexcitability and the subsequent neurodegeneration.

[0011] Typically, disease, trauma, or other lesions can lead to upregulation of A3AR on cells, thus providing an opportunity for selective A3AR agonist therapy or management of a variety of diseases and conditions afflicting humans and other animals.

[0012] There remains a need for adenosine receptor agonists for treating diseases. SUMMARY OF THE INVENTION

[0013] The novel chemical substances reported herein include selective ligands for the A3 adenosine receptor. The compounds include full agonists, partial agonists, and antagonists for functional assays of receptor activation. Many of these compounds have higher CNS penetration than earlier reported A3AR agonists and are particularly promising for treating neuroinflammation in the CNS. Selective antagonists of A3AR have potential therapeutic benefits. For example, topical administration of a selective A3AR antagonist can reduce intraocular pressure (Jacobson and Civan, J Ocular Pharmacol Ther 32:534 (2016)). Partial agonists are also of interest because one can potentially obtain therapeutic benefits with reduced tachyphylaxis, off-target activity, or biased activity towards one of several pathways coupled to receptor activation.

[0014] In some aspects, the present disclosure provides a compound represented by formula (II):

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] R 1 is selected from O, S, and C(R 21 )2;

[0018] R 51 is selected from -OR 30, optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)N(R 31 )2, -N(R 31 )C(O)OR 31 , -C(O)R 31 , C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, -NO2, -CN, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ;

[0019] L is selected from N and C(R 12 );

[0020] R 12 is selected from hydrogen, halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl, wherein the alkyl part of -O-C 1-6 alkyl and C 1-6 alkyl are each optionally substituted by one or more substituents selected from the following: halogen, -OH, -NH2, -NO2, -CN, -O-C 1-6 alkyl, C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring; wherein the C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the following: halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl;

[0021] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R1 When it is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen;

[0022] Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen;

[0023] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ;

[0024] L 2 is selected from a bond, O, NH and S;

[0025] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C1-C6 alkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring;

[0026] R 55 is selected from optionally substituted 3- to 6-membered heterocyclic rings, wherein the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents independently selected from: halogen, -OR 33 , -SR 33 , -S(O)2(R 33)、 -S(O)2N(R 33 )2、 -NR 33 S(O)2R 33 、 -C(O)N(R 33 )2、 -N(R 33 )C(O)R 33 、 -N(R 33 )C(O)N(R 33 )2、 -N(R 33 )C(O)OR 33 、 -N(R 33 )2、 -C(O)R 33 、 -C(O)OR 33 、 -OC(O)R 33 、 -OC(O)N(R 33 )2、 -NO2、 -CN、 oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0027] R 59 is selected from hydrogen, -OH, -NH2 and F; and

[0028] each R 30 、 R 31 、 R 32 and R 33 is independently selected from hydrogen and C optionally substituted by one or more substituents independently selected from the following 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0029] R 34 is selected from C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and

[0030] R 35 each independently selected from C optionally substituted by one or more substituents independently selected from the following each time it appears 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0031] In some embodiments, formula (II) is represented by formula (II’) or a pharmaceutically acceptable salt thereof:

[0032]

[0033] In some aspects, the present disclosure provides a compound represented by formula (I):

[0034]

[0035] or a pharmaceutically acceptable salt thereof, wherein:

[0036] Ring A is selected from a C5-C6 carbocyclic ring and a 5- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from R 51 ;

[0037] R 51 is selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, oxo group, -OR 31 , -SR 31 , -N(R 31 )2, -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31)C(O)R 31 、 -N(R 31 )C(O)N(R 31 )2、 -N(R 31 )C(O)OR 31 、 -C(O)R 31 、 C(O)OR 31 、 -OC(O)R 31 、 -OC(O)N(R 31 )2、 -NO2、 -CN、 optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ;

[0038] R 1 is selected from O, S and C(R 21 )2;

[0039] Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0040] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0041] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ;

[0042] L 2 is selected from a bond, O, NH and S;

[0043] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring;

[0044] R 55 is selected from optionally substituted 3- to 6-membered heterocyclic rings, wherein the 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 33 , -SR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )C(O)R 33 , -N(R 33 )C(O)N(R 33 )2, -N(R 33 )C(O)OR 33 , -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0045] R59 selected from hydrogen, -OH, -NH2, and F;

[0046] each R 30 、R 31 、R 32 and R 33 is independently selected, each time it appears, from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0047] R 34 is selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and

[0048] R 35 is independently selected, each time it appears, from C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0049] In some embodiments, formula (I) is represented by formula (I-A) or a pharmaceutically acceptable salt thereof:

[0050]

[0051] In some embodiments, Formula (I) or Formula (I-A) is represented by Formula (I-B) or a pharmaceutically acceptable salt thereof:

[0052]

[0053] wherein X is selected from O and NH.

[0054] In some aspects, the present disclosure provides a compound represented by Formula (I*):

[0055]

[0056] or a pharmaceutically acceptable salt thereof, wherein:

[0057] Ring A is selected from a C5-C6 carbocycle and a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 51 ;

[0058] R 51 is selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group, -C(O)R 30 , -C(O)OR 30 ; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and the 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ;

[0059] R 1 is selected from O, S and C(R 21 )2;

[0060] each R 21 is hydrogen, or R 22 and one R21 Together with the atoms to which they are bonded, form a 3-membered carbon ring and the other R 21 is hydrogen;

[0061] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atoms to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen;

[0062] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ;

[0063] L 2 is selected from a bond, O, NH and S;

[0064] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring;

[0065] R 55 is selected from hydrogen, -CN, C1-C6 haloalkyl, C1-C6 alkyl, -C(O)N(H)(R 11 ), and -CH2OR 12 ;

[0066] R59 Selected from hydrogen, -OH, -NH2, and F;

[0067] R 11 Selected from hydrogen, C1-C6 alkyl, and C3-C5 cycloalkyl;

[0068] R 12 Selected from hydrogen, C1-C6 alkyl, and -C(O)C1-C 10 alkyl;

[0069] Each R 30 、R 31 、R 32 and R 33 is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0070] R 34 Selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and

[0071] R 35 is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0072] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein or a salt of any of the compounds described herein and a pharmaceutically acceptable excipient.

[0073] In some aspects, the present disclosure provides a method for activating an A3 adenosine receptor, the method comprising administering to a subject in need thereof suffering from a condition a compound or salt described herein. In some embodiments, relative to the activation of A1, A 2A and A 2B receptors, the activation of the A3 adenosine receptor by the compound or salt is 3-fold or greater. In some embodiments, relative to the activation of A1, A 2A and A 2B receptors, the activation of the A3 adenosine receptor by the compound or salt is 5-fold or greater. In some embodiments, relative to the activation of A1, A 2A and A 2B receptors, the activation of the A3 adenosine receptor by the compound or salt is ten-fold or greater.

[0074] In some embodiments, the present disclosure provides a method for treating a condition selected from vascular inflammation, arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia, cerebral palsy, chronic hypoxia due to arteriovenous malformation and occlusive cerebral arterial disease, ischemia and reperfusion injury in skeletal muscle, severe neurological disorders associated with excitotoxicity, Parkinson's disease, Huntington's chorea, CNS diseases, heart diseases, kidney diseases, glaucoma, cancer, neuropathic pain, transient ischemic attack, bone marrow protection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis, and septic shock.

[0075] In some embodiments, the present disclosure provides a method for treating a condition selected from chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, neurodegeneration, drug-induced ototoxicity, spinocerebellar degeneration, symptoms associated with traumatic brain injury, chemotherapy-induced cognitive impairment, pain and discomfort of irritable bowel syndrome, and neuropathic pain.

[0076] Additional aspects and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes only illustrative embodiments of the present disclosure. As will be recognized, the present disclosure is capable of other and different embodiments, and its several details can be modified in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive.

[0077] Incorporated by reference

[0078] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If the publications and patents or patent applications incorporated herein by reference conflict with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material. Detailed Description

[0079] Although various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, variations, and substitutions may occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed.

[0080] A. Definitions

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0082] "Alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C 15 alkyl). In certain embodiments, the alkyl contains from one to thirteen carbon atoms (i.e., C1-C 13(alkyl). In certain embodiments, the alkyl contains from one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl contains from one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl contains from one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl contains from one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl contains from one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl contains one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl contains from five to fifteen carbon atoms (i.e., C5-C 15 (alkyl). In other embodiments, the alkyl contains from five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl contains from two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl contains from three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond.

[0083] The term "C x-y " when used in conjunction with chemical moieties such as alkyl, alkenyl or alkynyl is intended to include groups having from x to y carbons in the chain. For example, the term "C 1-6 alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group having from 1 to 6 carbons, including straight-chain alkyls and branched-chain alkyls. The term –C x-y alkylene– refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, –C 1-6 alkylene– may be selected from methylene, ethylene, propylene, butylene, pentylene and hexylene, any of which is optionally substituted.

[0084] "Alkoxy" refers to a group bonded through an oxygen atom of the formula –O-alkyl, where the alkyl is an alkyl chain as defined above.

[0085] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C 12(alkenyl). In certain embodiments, the alkenyl contains two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, the alkenyl contains two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl contains two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.

[0086] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms (i.e., C2-C 12 alkynyl). In certain embodiments, the alkynyl contains two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl contains two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl contains two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0087] The term "C x-y alkenyl" and "C x-y alkynyl" refer to unsaturated aliphatic groups that are substituted or unsubstituted and are similar to the alkyl groups described above in terms of length and possible substitution, but contain at least one double bond or triple bond, respectively. The term –C x-y alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, –C 2-6 alkenylene- can be selected from vinylene, propenylene, butenylene, pentenylene, and hexenylene, any of which is optionally substituted. The alkenylene chain can have one double bond or more than one double bond in the alkenylene chain. The term –C x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the alkenylene chain. For example, –C 2-6 alkenylene- can be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any of which is optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0088] "Alkylene" or "alkylene chain" refers to a divalent hydrocarbon chain that connects the remainder of the molecule to a group, consists only of carbon and hydrogen, contains no unsaturation, and preferably has a straight or branched chain with one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The connection points of the alkylene chain to the remainder of the molecule and to the group can be achieved through any two carbons within the chain. In certain embodiments, the alkylene contains one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene contains one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene contains one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene contains one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene contains one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene contains one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene contains one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene contains five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene contains two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene contains three to five carbon atoms (i.e., C3-C5 alkylene).

[0089] "Alkenylene" or "alkenylene chain" refers to a divalent hydrocarbon chain that connects the remainder of the molecule to a group, consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has a straight or branched chain with two to twelve carbon atoms. The alkenylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The connection points of the alkenylene chain to the remainder of the molecule and to the group can be achieved through any two carbons within the chain. In certain embodiments, the alkenylene contains two to ten carbon atoms (i.e., C2-C 10 alkenylene). In certain embodiments, the alkenylene contains two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, the alkenylene contains two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene contains two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene contains two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene contains two carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene contains five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene contains three to five carbon atoms (i.e., C3-C5 alkenylene).

[0090] "Alkynylene" or "alkynylene chain" refers to a divalent hydrocarbon chain that connects the remainder of the molecule to a group, consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has a straight or branched chain with two to twelve carbon atoms. The alkynylene chain is connected to the remainder of the molecule by a single bond and to the group by a single bond. The points of attachment of the alkynylene chain to the remainder of the molecule and to the group can be achieved through any two carbons within the chain. In certain embodiments, the alkynylene contains two to ten carbon atoms (i.e., C2-C 10 alkynylene). In certain embodiments, the alkynylene contains two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene contains two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene contains two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene contains two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene contains two carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene contains five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene contains three to five carbon atoms (i.e., C3-C5 alkynylene).

[0091] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n + 2)π electron system that conforms to Hückel's theory. The ring systems from which the aryl is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene.

[0092] "Aralkyl" refers to a group having the formula -R c -aryl, where R c is an alkylene chain as defined above, such as methylene, ethylene, etc.

[0093] "Arenyl" refers to a group having the formula –R d -aryl, where R d is an alkenylene chain as defined above. "Arylalkynyl" refers to a group having the formula -R e -aryl, where R e is an alkynylene chain as defined above.

[0094] "Carbocyclic ring" refers to a saturated, unsaturated or aromatic ring, wherein each atom of the ring is carbon. The carbocyclic ring may include a 3- to 10-membered monocyclic ring, a 6- to 12-membered bicyclic ring, and a 6- to 12-membered bridged ring. Each ring of the bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring such as phenyl may be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of the carbocyclic ring when the valences permit. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0095] The term "unsaturated carbocyclic ring" refers to a carbocyclic ring having at least one degree of unsaturation and not including an aromatic carbocyclic ring. Examples of unsaturated carbocyclic rings include cyclohexadiene, cyclohexene, and cyclopentene.

[0096] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring systems or bridged ring systems, and preferably having three to twelve carbon atoms. In certain embodiments, the cycloalkyl contains three to ten carbon atoms. In other embodiments, the cycloalkyl contains five to seven carbon atoms. The cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.

[0097] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring systems or bridged ring systems, preferably having three to twelve carbon atoms, and containing at least one double bond. In certain embodiments, the cycloalkenyl contains three to ten carbon atoms. In other embodiments, the cycloalkenyl contains five to seven carbon atoms. The cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0098] "Cycloalkylalkyl" refers to a group having the formula –R c -cycloalkyl, wherein R c is an alkylene chain as described above.

[0099] "Cycloalkylalkoxy" refers to a group bonded through an oxygen atom of the formula –O-R c -cycloalkyl, wherein R c is an alkylene chain as described above.

[0100] "Halogen" or "halide" refers to a halogen substituent, such as bromine, chlorine, fluorine, and iodine substituents.

[0101] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes, and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethanes, 2-haloethanes, 1,2-dihaloethanes, 1-halopropanes, 2-halopropanes, 3-halopropanes, 1,2-dihalopropanes, 1,3-dihalopropanes, 2,3-dihalopropanes, 1,2,3-trihalopropanes, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted with more than one halogen group, each halogen can be independently selected, such as 1-chloro,2-fluoroethane.

[0102] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluorines, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0103] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amine groups, such as propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine, and the like.

[0104] "Alkoxyalkyl" refers to an alkyl group as defined above that is substituted with one or more alkoxy groups, such as methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0105] "Cyanoalkyl" refers to an alkyl group as defined above that is substituted with one or more cyano groups, such as acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0106] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups, such as propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0107] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring that contains one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocycles, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles can be fused, bridged, or spiro ring systems. In some cases, a spiro heterocycle has at least two molecular rings that share only one common atom. Spiro heterocycles contain at least one heteroatom.

[0108] "Hetocyclylene" means a divalent heterocyclic ring that attaches the remainder of the molecule to the group.

[0109] "Heteroaryl" or "aromatic heterocycle" means a group derived from a heteroaromatic ring group containing from one to eleven carbon atoms and at least one heteroatom, where each heteroatom is independently selected from N, O, and S. As used herein, the heteroaryl ring is selected from monocyclic or bicyclic and fused or bridged ring system rings, where at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n + 2)π electron system in accordance with Hückel's theory. The heteroatoms in the heteroaryl may optionally be oxidized. If present, then one or more nitrogen atoms are optionally quaternized. Where valence permits, the heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzothiazole, and imidazopyridine.

[0110] "X-membered heteroaryl" is the number of atoms within the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 atoms within the ring, such as triazole, oxazole, thiophene, etc.

[0111] "Heterocycloalkyl" means a 3- to 12-membered non-aromatic ring group containing from two to twelve carbon atoms and at least one heteroatom, where each heteroatom is independently selected from N, O, Si, P, B, and S atoms. The heterocycloalkyl is selected from monocyclic or bicyclic and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl are optionally oxidized. If present, then one or more nitrogen atoms are optionally quaternized. The heterocycloalkyl is partially or fully saturated. Where valence permits, the heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl such as any carbon or nitrogen atom of the heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, dioxolanyl, thienyl[1,3]dithiacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithiacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0112] The term "unsaturated heterocycle" means a heterocycle having at least one degree of unsaturation and not including an aromatic heterocycle. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle may optionally be substituted with one or more substituents (such as those described herein).

[0113] The term "substituted" refers to a substituent on one or more carbons or a heteroatom that can be substituted, such as hydrogen on NH, having a replacement structure. It should be understood that "substituted" or "substituted with" includes the implicit condition that such substitution conforms to the allowable valences of the atom being substituted and the substituent, and the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a substituent on a moiety that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thio group. As used herein, the term "substituted" is considered to include all allowable substituents of an organic compound. In a broad aspect, allowable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For a suitable organic compound, the allowable substituents can be one or more and can be the same or different. For the purposes of this disclosure, a heteroatom such as nitrogen can have a hydrogen substituent and / or any allowable substituent of an organic compound that conforms to the valence of the heteroatom.

[0114] In some embodiments, the substituent can include any of the substituents described herein, for example: halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximino (=N-OH), hydrazino (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t Ra (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl and heterocycle, any of which may optionally be substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo group (=O), thioxo group (=S), cyano group (-CN), nitro group (-NO2), imino group (=N-H), oximino group (=N-OH), hydrazino group (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b-S(O) t N(R a )2 (where t is 1 or 2); wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, and wherein each R a is optionally substituted, when valence permits, with: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo group (=O), thioxo group (=S), cyano group (-CN), nitro group (-NO2), imino group (=N-H), oxime group (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2)、-R b -S(O) t R a (where t is 1 or 2)、-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b is independently selected from a direct bond or a straight-chain or branched alkylene, alkenylene, or alkynylene chain, and each R cis a straight or branched alkylene, alkenylene or alkynylene chain.

[0115] Unless the context clearly dictates otherwise, as used in the specification and claims, the singular forms "a", "an", and "the" include plural referents.

[0116] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0117] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration that are typically effected by injection and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0118] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0119] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances for pharmaceutical formulations.

[0120] In certain embodiments, as used herein, the terms "prevent" or "preventing" in relation to a disease or disorder may mean that in a statistical sample, a compound reduces the occurrence of a disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a disorder or condition or reduces the severity of said one or more symptoms relative to an untreated control sample.

[0121] As used herein, the term "treat" or "treating" or "treatment" may include alleviating, attenuating, or ameliorating symptoms of a disease or disorder; preventing additional symptoms; improving or preventing the underlying cause of symptoms; inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder; alleviating a disease or disorder; causing regression of a disease or disorder; alleviating a condition caused by a disease or disorder; or prophylactically and / or therapeutically halting the symptoms of a disease or disorder.

[0122] B. Compounds of the present disclosure

[0123] In one aspect, the present disclosure provides a compound represented by formula (II):

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein:

[0126] R 1 is selected from O, S, and C(R 21 )2;

[0127] R 51 is selected from -OR 30 , optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)N(R 31 )2, -N(R 31 )C(O)OR 31 , -C(O)R 31 , C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, -NO2, -CN, optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 ;

[0128] L is selected from N and C(R 12 );

[0129] R 12 is selected from hydrogen, halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl, and C 1-6 alkyl, wherein the alkyl moiety of -O-C 1-6 alkyl and the C 1-6 alkyl are each optionally substituted by one or more substituents selected from the following: halogen, -OH, -NH2, -NO2, -CN, -O-C 1-6 alkyl, C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring; wherein the C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the following: halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl;

[0130] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are attached form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0131] Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are attached form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0132] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ;

[0133] L 2 is selected from a bond, O, NH and S;

[0134] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6Carbocyclic rings and 3- to 6-membered heterocyclic rings;

[0135] R 55 is selected from optionally substituted 3- to 6-membered heterocyclic rings, wherein said 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 33 , -SR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )C(O)R 33 , -N(R 33 )C(O)N(R 33 )2, -N(R 33 )C(O)OR 33 , -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0136] R 59 is selected from hydrogen, -OH, -NH2 and F; and

[0137] each R 30 , R 31 , R 32 and R 33 is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, wherein C 3-6The carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0138] R 34 is selected from C 3-6 a carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy; and

[0139] R 35 is, each time it appears, independently selected from C optionally substituted with one or more substituents independently selected from the following 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 a carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0140] In some embodiments, formula (II) is represented by formula (II') or a pharmaceutically acceptable salt thereof:

[0141]

[0142] In some embodiments, for the compound or salt of formula (II) or formula (II'), for R 55 , the 3- to 6-membered heterocyclic ring has at least 1 heteroatom. In some cases, for R 55 , the 3- to 6-membered heterocyclic ring has at least 1 nitrogen atom. In some cases, R 55 is a 5- to 6-membered heterocyclic ring. In some cases, R 55 is a 5-membered heterocyclic ring. In some cases, for R 55 , the heterocyclic ring has at least 2 nitrogen atoms. In some cases, for R 55 , the heterocyclic ring has 3 nitrogen atoms. In some cases, for R 55 , the heterocyclic ring is unsubstituted.

[0143] In some embodiments, for the compound or salt of formula (II) or formula (II’), for R 55 , the 3- to 6-membered heterocycle has at least 1 nitrogen atom. In some cases, R 55 is an optionally substituted 5- to 6-membered heterocycle. In some cases, R 55 is selected from optionally substituted 5- to 6-membered heteroaryl. In some cases, R 55 is an optionally substituted 5- to 6-membered saturated heterocycle. In some cases, R 55 is an optionally substituted 5- to 6-membered unsaturated heterocycle. In some cases, for R 55 , the 5- to 6-membered heterocycle has at least 2 nitrogen atoms. In some cases, for R 55 , the 5- to 6-membered heterocycle has at least 3 nitrogen atoms. In some cases, R 55 is an optionally substituted 6-membered heterocycle. In some cases, R 55 is an optionally substituted 5-membered heterocycle. In some cases, R 55 is an unsubstituted 5-membered heterocycle. In some cases, R 55 is an unsubstituted 6-membered heterocycle. In some cases, R 55 is a substituted 5-membered heterocycle. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is which is optionally substituted. In some cases, R 55 is which is optionally substituted. In some cases, the optional substituents are independently selected from one or more C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl. In some cases, the optional substituents are independently selected from one or more C 1-6 alkyl. In some cases, R 55 is selected from In some cases, R55 Selected from In some cases, R 55 Selected from In some cases, R 55 Selected from In some cases, R 55 Selected from In some cases, R 55 is In some cases, R 55 is

[0144] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 55 is selected from optionally substituted 3- to 6-membered heterocycles. In some cases, R 55 is selected from optionally substituted 5- to 6-membered heteroaryl. In some cases, R 55 is an optionally substituted 5- to 6-membered saturated heterocycle. In some cases, R 55 is an optionally substituted 5- to 6-membered unsaturated heterocycle. In some cases, the heterocycle contains at least 1, 2, 3, or 4 heteroatoms. In some cases, the heterocycle contains at most 1, 2, 3, or 4 heteroatoms. In some cases, the heterocycle contains 1, 2, 3, or 4 heteroatoms. In some cases, the heteroatoms are selected from nitrogen and oxygen. In some cases, each of the heteroatoms is nitrogen. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, one or more optional substituents are independently selected from halogen, -OR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl1-6 Cyanoalkyl and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from halogen, -OH, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from C 1-6 alkyl. In some cases, one or more optional substituents are independently selected from methyl. In some cases, the heterocycle is unsubstituted.

[0145] In some embodiments, for the compound or salt of formula (II) or formula (II’), R 55 is

[0146] In some embodiments, for the compound or salt of formula (II) or formula (II’), R 52 is selected from hydrogen, halogen, and -L 2 -Y 2 . In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is hydrogen. In some cases, R 52 is -L 2 -Y 2 . In some cases, R 52 is -L 2 -Y 2 wherein L 2 is a bond. In some cases, R 52 is CN.

[0147] In some embodiments, for the compound or salt of formula (II) or formula (II’), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 wherein L 2 is a bond and Y 2 is optionally substituted with one or more independently selected from C 3-6A C2-C6 alkynyl group substituted with substituents of a carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is an unsubstituted C 3-6 carbocyclic ring-substituted C2-C6 alkynyl group. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine.

[0148] In some embodiments, for a compound or salt of formula (II) or formula (II’), L 2 is selected from a bond and O. In some cases, L 2 is a bond. In some cases, L 2 is O.

[0149] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 52 is selected from hydrogen, halogen, and -L 2 -Y 2 . In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is hydrogen. In some cases, R 52 is -L 2 -Y 2 . In some cases, R 52 is -L 2 -Y 2 , wherein L 2 is a bond.

[0150] In some embodiments, for a compound or salt of formula (II) or formula (II’), L 2 is a bond.

[0151] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 , wherein L 2 is a bond and Y 2 is optionally substituted with one or more independently selected from C 3-6A C2-C6 alkynyl group substituted with a substituent of a carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is an unsubstituted C 3-6 carbocyclic ring-substituted C2-C6 alkynyl. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine. In some cases, R 52 is CN.

[0152] In some embodiments, for the compound or salt of formula (II) or formula (II’), L 2 is a bond and Y 2 is an optionally substituted 3- to 6-membered heterocyclic ring. In some cases, Y 2 is an optionally substituted 5-membered heterocyclic ring. In some cases, the 5-membered heterocyclic ring is selected from each of which is optionally substituted. In some cases, the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0153] In some embodiments, for a compound or salt of formula (II) or formula (II’), L is selected from N and C(R 12 ). In some cases, L is N. In some cases, L is C(R 12 ). In some cases, R 12 is hydrogen. In some cases, R 12 is selected from hydrogen, halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl. In some cases, L is CH.

[0154] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 1 is selected from O and C(R 21 )2. In some cases, R 1 is O. In some cases, R 1 is C(R 21 )2. In some cases, R 1 is C(R 21 )2, and R 22 and one R 21 together with the atom to which they are attached form a 3-membered carbon ring and the other R 21 is hydrogen. In some cases, R 1 is O and R 22 is hydrogen. In some cases, R 1 is oxygen and R 22 and R 55 are each hydrogen.

[0155] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

[0156] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 is selected from C1-C6 alkyl substituted with one or more C 3-6 carbocycles, wherein the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from halogen. In some cases, the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from halogen and -OR 33 . In some cases, R 51 is selected from C1-C6 alkyl substituted with a phenyl group, wherein the phenyl group is substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, R 51 is selected from C1-C6 alkyl substituted with a phenyl group, wherein the phenyl group is substituted with one or more substituents independently selected from halogen. In some cases, R 51 is In some cases, R 51 is selected from In some cases, R 51 is selected from In some cases, R 51 is selected from

[0157] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen and optionally substituted C 3-6 carbocycles, wherein the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, R 51Selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen. In some cases, R 51 Selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from fluorine. In some cases, R 51 Selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with two or more substituents independently selected from fluorine. In some cases, R 51 Selected from C1-C6 alkyl. In some cases, R 51 Selected from C2-C6 alkyl. In some cases, R 51 is methyl. In some cases, R 51 is ethyl. In some cases, R 51 is propyl. In some cases, R 51 Selected from CH2CH3, CH2CFH2, CH2CF2H, and CH2CF3.

[0158] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 Selected from optionally substituted C 3-6 carbocycle. In some cases, R 51 is

[0159] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 33 Selected from C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 33 Selected from C 1-6An alkyl group, wherein each of the 5- to 6-membered heterocycles is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy. In some cases, R 33 is selected from C 1-6 alkyl groups substituted by one or more substituents independently selected from 5-membered heterocycles, wherein the 5-membered heterocycle is optionally substituted by one or more substituents independently selected from C1-C6 alkyl groups. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle is

[0160] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 33 is selected from C 1-6 alkyl groups substituted by 3- to 6-membered heterocycles, wherein the 3- to 6-membered heterocycle is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some cases, R 33 is selected from C 1-6 alkyl groups substituted by 5-membered heterocycles, wherein the 5-membered heterocycle is substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 aminoalkyl, and C1-C6 haloalkyl.

[0161] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 is selected from

[0162] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 51 is optionally substituted C1-C6 alkyl. In some cases, R 51 is C1-C6 alkyl optionally substituted by fluorine and a C 3-6 carbocycle, wherein the C 3-6 carbocycle is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 31 , -N(R 31 )2, -NO2, -CN, and C 1-3 alkyl. In some cases, R 51 is C1-C6 alkyl optionally substituted by fluorine and phenyl, wherein the phenyl is optionally substituted by one or more substituents independently selected from halogen.

[0163] In some embodiments, for a compound or salt of formula (II) or formula (II’), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 , where L 2 is a bond and Y 2 is a C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, where C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is a C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocyclic ring. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine.

[0164] In some embodiments, for a compound or salt of formula (II) or formula (II’), L 2 is a bond and Y 2 is selected from C 3-6 carbocyclic rings. In some cases, R 52 is

[0165] In some embodiments, for a compound or salt of formula (II) or formula (II’), L 2 is a bond and Y 2 is an optionally substituted 3- to 6-membered heterocyclic ring. In some cases, Y 2 is an optionally substituted 5-membered heterocyclic ring. In some cases, the 5-membered heterocyclic ring is selected from each of which is optionally substituted. In some cases, the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic rings, and 3- to 6-membered heterocyclic rings, where C3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 、-N(R 32 )2、-NO2、-CN、oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0166] In some embodiments, for the compounds or salts of formula (II) or formula (II’), R 30 、R 31 、R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 30 、R 31 、R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring. In some cases, R 30 、R 31 、R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 30 is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R31 independently selected from hydrogen and C 1-6 alkyl at each occurrence. In some cases, each R 32 is independently selected from hydrogen and C 1-6 alkyl at each occurrence. In some cases, each R 33 is independently selected from hydrogen and C 1-6 alkyl at each occurrence.

[0167] In some embodiments, for a compound or salt of formula (II) or formula (II’), each R 34 is selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some cases, R 34 is selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring. In some cases, each R 34 is selected from C 3-6 carbocyclic ring. In some cases, R 34 is selected from 3- to 6-membered heterocyclic ring.

[0168] In some embodiments, for a compound or salt of formula (II) or formula (II’), each R 35 is independently selected at each occurrence from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring. In some cases, each R 35 is independently selected at each occurrence from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, OH, -CN, -NO2, -NH2, oxo group, and -O-C 1-6 alkyl. In some cases, each R 35 is independently selected at each occurrence from C 1-6 alkyl.

[0169] In another aspect, the present disclosure provides a compound represented by formula (I):

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein:

[0172] Ring A is selected from a C5-C6 carbocyclic ring and a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from R 51 ;

[0173] R 51 is selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, oxo group, -OR 31 , -SR 31 , -N(R 31 )2, -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)N(R 31 )2, -N(R 31 )C(O)OR 31 , -C(O)R 31 , C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, -NO2, -CN, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ;

[0174] R 1 is selected from O, S and C(R 21 )2;

[0175] Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0176] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen;

[0177] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen, and -L 2 -Y 2 ;

[0178] L 2 is selected from a bond, O, NH, and S;

[0179] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring, and 3- to 6-membered heterocyclic ring;

[0180] R 55 is selected from optionally substituted 3- to 6-membered heterocyclic rings, wherein the 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 33 , -SR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )C(O)R 33 , -N(R33 )C(O)N(R 33 )2, -N(R 33 )C(O)OR 33 , -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0181] R 59 is selected from hydrogen, -OH, -NH2, and F;

[0182] Each R 30 , R 31 , R 32 and R 33 , upon each occurrence, is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0183] R 34 is selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and

[0184] R 35Each occurrence is independently selected from C optionally substituted by one or more substituents independently selected from the following 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein C 3-6 the carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0185] In some embodiments, for the compound or salt of formula (I), R 1 is selected from O and C(R 21 )2. In some cases, R 1 is C(R 21 )2, and R 22 and one R 21 together with the atom to which they are attached form a 3-membered carbocycle and the other R 21 is hydrogen.

[0186] In some embodiments, for the compound or salt of formula (I), R 59 is selected from -OH and -NH2. In some cases, R 59 is -OH. In some cases, R 59 is the same. In some cases, each R 59 is different.

[0187] In some embodiments, formula (I) is represented by formula (I-A) or a pharmaceutically acceptable salt thereof:

[0188]

[0189] In some embodiments, for the compound or salt of formula (I) or formula (I-A), ring A is selected from C5-C6 carbocycles and 5- to 6-membered heterocycles, each of which is optionally substituted by one or more substituents independently selected from R 51 . In some cases, ring A is selected from optionally substituted 5- to 6-membered heterocycles. In some cases, ring A is selected from optionally substituted 5-membered heterocycles. In some cases, the heterocycle contains at least 1 or 2 heteroatoms. In some cases, the heterocycle contains 1 or 2 heteroatoms. In some cases, the heteroatoms are selected from oxygen and nitrogen. In some cases, the heteroatom is selected from nitrogen. In some cases, ring A is selected from optionally substituted C5-C6 carbocycles. In some cases, ring A is selected from optionally substituted C5 carbocycles. In some cases, ring A is selected from Each of them is optionally substituted. In some cases, ring A is selected from It is optionally substituted. In some cases, ring A is selected from Each of them is optionally substituted.

[0190] In some cases, ring A is selected from

[0191] In some cases, ring A is selected from Each of them is optionally substituted.

[0192] In some embodiments, formula (I) or formula (I-A) is represented by formula (I-B) or a pharmaceutically acceptable salt thereof:

[0193]

[0194] wherein X is selected from O and NH.

[0195] In some embodiments, for the compound or salt of formula (I-B), X is NH. In some cases, X is O.

[0196] In some embodiments, for the compound or salt of formula (I), formula (I-A) or formula (I-B), for R 55 , the 3- to 6-membered heterocycle has at least 1 nitrogen atom. In some cases, R 55 is an optionally substituted 5- to 6-membered heterocycle. In some cases, R 55 is an optionally substituted 5- to 6-membered saturated heterocycle. In some cases, R 55 is an optionally substituted 5- to 6-membered unsaturated heterocycle. In some cases, the heterocycle of R 55 is aromatic. In some cases, R 55 is selected from optionally substituted 5- to 6-membered heteroaryl. In some cases, for R 55 , the 5- to 6-membered heterocycle has at least 2 nitrogen atoms. In some cases, for R 55 , the 5- to 6-membered heterocycle has at least 3 nitrogen atoms. In some cases, R 55 is an optionally substituted 6-membered heterocycle. In some cases, R 55 is an optionally substituted 5-membered heterocycle. In some cases, R 55 is an unsubstituted 5-membered heterocycle. In some cases, R 55 is an unsubstituted 6-membered heterocycle. In some cases, R 55 is a substituted 5-membered heterocycle. In some cases, R 55 is selected from Each of them is optionally substituted.

[0197] In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is which is optionally substituted.

[0198] In some cases, R 55 is which is optionally substituted. In some cases, the optional substituent is independently selected from one or more C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl. In some cases, the optional substituent is independently selected from one or more C 1-6 alkyl. In some cases, R 55 is selected from In some cases, R 55 is selected from In some cases, R 55 is selected from In some cases, R 55 is selected from In some cases, R 55 is selected from In some cases, R 55 is In some cases, R 55 is

[0199] In some embodiments, for the compound or salt of formula (I-B), X is NH. In some cases, X is O.

[0200] In some embodiments, for the compound or salt of formula (I), formula (I-A) or formula (I-B), R 55 is selected from an optionally substituted 3- to 6-membered heterocycle. In some cases, R 55 is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, R 55 is an optionally substituted 5- to 6-membered saturated heterocycle. In some cases, R 55is an optionally substituted 5- to 6-membered unsaturated heterocycle. In some cases, the heterocycle contains at least 1, 2, 3, or 4 heteroatoms. In some cases, the heterocycle contains at most 1, 2, 3, or 4 heteroatoms. In some cases, the heterocycle contains 1, 2, 3, or 4 heteroatoms. In some cases, the heteroaryl contains at least 1, 2, 3, or 4 heteroatoms. In some cases, the heteroatoms are selected from nitrogen and oxygen. In some cases, each of the heteroatoms is nitrogen. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, R 55 is selected from each of which is optionally substituted. In some cases, one or more optional substituents are independently selected from halogen, -OR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from halogen, -OH, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 1-6 haloalkyl. In some cases, one or more optional substituents are independently selected from C 1-6Alkyl. In some cases, one or more optional substituents are independently selected from methyl. In some cases, the heterocycle is unsubstituted. In some cases, R 55 of the heterocycle is heteroaryl (e.g., 5- to 6-membered heteroaryl).

[0201] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), for R 55 , the 3- to 6-membered heterocycle has at least 1 nitrogen atom. In some cases, for R 55 , the 5- to 6-membered heterocycle. In some cases, R 55 is a 5-membered heterocycle. In some cases, for R 55 , the heterocycle has at least 2 nitrogen atoms. In some cases, for R 55 , the heterocycle has 3 nitrogen atoms. In some cases, for R 55 , the heterocycle is unsubstituted. In some cases, R 55 is

[0202] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 51 is selected from C1-C6 alkyl substituted by one or more C 3-6 carbocycles, wherein the C 3-6 carbocycle is optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 . In some cases, the C 3-6 carbocycle is optionally substituted by one or more substituents independently selected from halogen. In some cases, the C 3-6 carbocycle is optionally substituted by one or more substituents independently selected from halogen and -OR 33 . In some cases, the C 3-6 carbocycle is substituted by one or two halogen atoms. In some cases, the C 3-6 carbocycle is substituted by two halogen atoms. In some cases, R 51 is In some cases, R 51 is selected from In some cases, R 51 is selected from In some cases, R 51 is selected from

[0203] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen and optionally substituted C 3-6 carbocycles, where C 3-6 carbocycles are optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen. In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from fluorine. In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with two or more substituents independently selected from fluorine. In some cases, R 51 is selected from C1-C6 alkyl. In some cases, R 51 is selected from C2-C6 alkyl. In some cases, R 51 is methyl. In some cases, R 51 is ethyl. In some cases, R 51 is propyl. In some cases, R 51 is selected from CH2CH3, CH2CFH2, CH2CF2H, and CH2CF3. In some cases, the C1-C6 alkyl is substituted.

[0204] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 51 is selected from halogen, -OR 30 , -N(R 30 )2, -NO2, -CN, oxo; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocycles, and optionally substituted 3- to 6-membered heterocycles, each of which is optionally substituted with one or more substituents independently selected from: halogen, oxo, -OR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6Carbocyclic rings and optionally substituted 3- to 6-membered heterocyclic rings, wherein C 3-6 The carbocyclic rings and 3- to 6-membered heterocyclic rings are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from the following: halogen, oxo group, -OR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, and -CN. In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from the following: halogen, oxo group, -OH, and -O-C1-C6 alkyl. In some cases, R 51 is selected from substituted C1-C6 alkyl, and the C1-C6 alkyl is substituted by one or more substituents independently selected from halogen, oxo group, and -OH. In some cases, R 51 is selected from substituted C1-C6 alkyl, and the C1-C6 alkyl is substituted by one or more substituents independently selected from halogen. In some cases, R 51 is selected from substituted C1-C6 alkyl, and the C1-C6 alkyl is substituted by one or more substituents independently selected from hydroxyl group and =O. In some cases, R 51 is selected from substituted C1-C6 alkyl, and the C1-C6 alkyl is substituted by one or more substituents independently selected from hydroxyl group. In some cases, R 51 is selected from substituted C1-C6 alkyl, and the C1-C6 alkyl is substituted by one or more substituents independently selected from =O. In some cases, R 51 is selected from In some cases, R 51 is In some cases, R 51 is In some cases, R 51 is In some cases, R 51 is selected from C1-C6 alkyl. In some cases, R 51 is

[0205] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -OH, -CN, -NO2, -NH2, oxo, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from 5- to 6-membered heterocyclic rings, wherein the 5- to 6-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some cases, R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from 5-membered heterocyclic rings, wherein the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkyl. In some cases, the heterocyclic ring has at least one nitrogen atom. In some cases, the heterocyclic ring has at least one oxygen atom. In some cases, the heterocyclic ring is

[0206] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 33 is selected from C 1-6 alkyl substituted with a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some cases, R 33 is selected from C 1-6 alkyl substituted with a 5-membered heterocyclic ring, wherein the 5-membered heterocyclic ring is substituted with one or more substituents independently selected from: C1-C6 alkyl, C1-C6 aminoalkyl, and C1-C6 haloalkyl. In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 51Selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 . In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from optionally substituted C 3-6 carbocycle, wherein the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 . In some cases, R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle.

[0207] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -OH, -CN, -NO2, -NH2, oxo, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 .

[0208] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 33 is selected from C 1-6 alkyl substituted with a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0209] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), L 2 is selected from a bond and O. In some cases, L 2 is a bond. In some cases, L 2 is O.

[0210] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 52 is selected from hydrogen, halogen, and -L 2 -Y 2 . In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is hydrogen. In some cases, R 52 is -L 2 -Y 2 . In some cases, R 52 is L 2 -Y 2 , where L 2 is a bond.

[0211] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), L 2 is a bond.

[0212] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 , where L 2 is a bond and Y 2 is a C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocycles and 3- to 6-membered heterocycles, wherein the C 3-6 carbocycles and 3- to 6-membered heterocycles are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is a C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocycle. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine. In some cases, R 52 is CN.

[0213] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), L 2 is a bond and Y 2 is an optionally substituted 3- to 6-membered heterocycle. In some cases, Y 2 is an optionally substituted 5-membered heterocycle. In some cases, the 5-membered heterocycle is selected from each of which is optionally substituted. In some cases, the 5-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocycles and 3- to 6-membered heterocycles, wherein the C 3-6The carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, the 5-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0214] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 , where L 2 is a bond and Y 2 is a C2-C6 alkynyl optionally substituted with one or more substituents independently selected from substituents of a C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is a C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocyclic ring. In some cases, R 52 is

[0215] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), L 2 is -O- and Y 2 is selected from C1-C6 alkyl. In some cases, R 52 is -O-CH2-CH3.

[0216] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is hydrogen.

[0217] In some embodiments, for a compound or salt of formula (I), formula (I-A), or formula (I-B), R52 is -CN.

[0218] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 52 is -NH2.

[0219] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 52 is selected from halogen, -CN, -NH2 and L 2 -Y 2 ; wherein L 2 is selected from O and a bond, where L 2 is selected from O, Y 2 is selected from C1-C6 alkyl, and wherein when L 2 is a bond, Y 2 is selected from C2-C6 alkynyl, the C2-C6 alkynyl being substituted by C 3-6 carbocyclic ring.

[0220] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 52 is selected from -Cl, -CN, -NH2, In some cases, R 52 is selected from -Cl, -CN and -NH2. In some cases, R 52 is selected from

[0221] In some embodiments, for a compound or salt of formula (I), formula (I-A) or formula (I-B), R 30 , R 31 , R 32 and R 33 each independently at each occurrence is selected from hydrogen and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 30 , R 31 , R 32 and R33 Each occurrence is independently selected from hydrogen and C optionally substituted with one or more substituents independently selected from the following: 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring. In some cases, R 30 , R 31 , R 32 and R 33 Each occurrence is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 30 Each occurrence is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 31 Each occurrence is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 32 Each occurrence is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 33 Each occurrence is independently selected from hydrogen and C 1-6 alkyl.

[0222] On the other hand, the present disclosure provides a compound represented by formula (I*):

[0223]

[0224] or a pharmaceutically acceptable salt thereof, wherein:

[0225] Ring A is selected from a C5-C6 carbocyclic ring and a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from R 51 ;

[0226] R 51 is selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group, -C(O)R 30 , -C(O)OR 30 , optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31, -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ;

[0227] R 1 is selected from O, S and C(R 21 )2;

[0228] Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0229] When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen;

[0230] R 52 is selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ;

[0231] L 2 is selected from a bond, O, NH and S;

[0232] Y 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring;

[0233] R 55 selected from hydrogen, -CN, C1-C6 haloalkyl, C1-C6 alkyl, -C(O)N(H)(R 11 ) and -CH2OR 12 ;

[0234] each R 59 is independently selected from hydrogen, -OH, -NH2 and F;

[0235] R 11 selected from hydrogen and C1-C6 alkyl;

[0236] R 12 selected from hydrogen, C1-C6 alkyl and -C(O)C1-C 10 alkyl;

[0237] each R 30 , R 31 , R 32 and R 33 is independently selected from hydrogen and C optionally substituted by one or more substituents independently selected from the following each time it appears 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ;

[0238] R 34 selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and

[0239] R 35 each independently selected from C optionally substituted with one or more substituents independently selected from the following each time it appears 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0240] In some embodiments, for the compound or salt of formula (I*), ring A is a 5- to 6-membered heterocyclic ring, which is each optionally substituted with one or more substituents independently selected from R 51 ; each R 51 is selected from optionally substituted C1-C6 alkyl; R 55 is selected from hydrogen, -C(O)N(H)(Me), and -CH2OH; each R 59 is selected from -OH; R 1 is C(R 21 )2 and R 22 and one R 21 together with the atoms to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen. In some cases, ring A is selected from which is optionally substituted with one or more substituents independently selected from R 51 ; R 52 is selected from halogen; R 51 is selected from C1-C6 alkyl; R 55 is selected from hydrogen; each R 59 is selected from -OH; and, R 1 is C(R 21 )2 and R 22 and one R 21 together with the atoms to which they are bonded form a 3-membered carbocyclic ring and the other R 21 is hydrogen. In some cases, ring A is selected from

[0241] In some embodiments, for the compound or salt of formula (I*), R1 Selected from O and C(R 21 )2. In some cases, R 1 is C(R 21 )2. In some cases, R 1 is C(R 21 )2, and R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen. In some cases, R 1 is oxygen. In some cases, R 1 is oxygen and R 22 and R 55 are each hydrogen. In some cases, R 1 is O and R 22 is hydrogen.

[0242] In some embodiments, for the compound or salt of formula (I*), R 1 is O, R 22 is hydrogen, and R 55 is selected from hydrogen, -C(O)N(H)(R 11 ) and -CH2OR 12 . In some cases, R 55 is selected from -C(O)N(H)(R 11 ) and -CH2OR 12 . In some cases, R 55 is selected from hydrogen, -C(O)N(H)(Me) and -CH2OH. In some cases, R 55 is selected from -C(O)N(H)(Me) and -CH2OH. In some cases, R 55 is selected from hydrogen and -C(O)N(H)(R 11 ). In some cases, R 55 is -C(O)N(H)(R 11 ). In some cases, R 55 is hydrogen. In some cases, R 11 is selected from hydrogen and C1-C3 alkyl. In some cases, R 11 is selected from C1-C3 alkyl. In some cases, R 55 is selected from hydrogen.

[0243] In some embodiments, for the compound or salt of formula (I*), ring A is selected from optionally substituted 5- to 6-membered heterocycles. In some cases, ring A is selected from optionally substituted 5- to 6-membered heterocycles, wherein the heterocycle contains 1 to 2 nitrogen atoms. In some cases, ring A is selected from each of which is optionally substituted with one or more independently selected from R 51is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent.

[0244] In some embodiments, for a compound or salt of formula (I*), ring A is selected from an optionally substituted 5- to 6-membered heterocycle, wherein the heterocycle contains 1 nitrogen atom. In some cases, ring A is selected from each of which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent.

[0245] In some embodiments, for a compound or salt of formula (I*), ring A is selected from an optionally substituted 5-membered heterocycle, wherein the heterocycle contains 1 to 2 nitrogen atoms. In some cases, ring A is selected from each of which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from each of which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent. In some cases, ring A is selected from which is optionally substituted by one or more substituents independently selected from R 51 is substituted by a substituent.

[0246] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 51Selected from optionally substituted C1-C6 alkyl. In some cases, the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 . In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from optionally substituted C 3-6 carbocycle, wherein the C 3-6 carbocycle is optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, and -OR 33 .

[0247] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R33 selected from C substituted with one or more substituents independently selected from the following 1-6 alkyl: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 33 is selected from C substituted with a 3- to 6-membered heterocyclic ring 1-6 alkyl, wherein the 3- to 6-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0248] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), each R 51 is independently selected from -OH, =O and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, =O, phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R 51 is independently selected from -CH3, -OH and =O. In some cases, each R 51 is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from halogen, =O, phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, wherein each R 51 is selected from -CH3, In some cases, each R 51 is independently selected from C1-C6 alkyl. In some cases, each R 51 is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen. In some cases, each R 51Independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen, =O, phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R 51 Independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with a phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen. In some cases, the phenyl is unsubstituted.

[0249] In some embodiments, for a compound or salt of formula (I*), ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is selected from In some cases, ring A is In some cases, ring A is In some cases, ring A is In some cases, ring A is

[0250] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 51 is selected from In some cases, R 51 is selected from In some cases, R 51 is In some cases, R 51 is In some cases, R 51 is

[0251] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 51Selected from optionally substituted C1-C6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen. In some embodiments, R 51 Selected from C1-C6 alkyl substituted by one or more substituents independently selected from halogen. In some embodiments, R 51 Selected from C1-C3 alkyl substituted by one or more substituents independently selected from halogen. In some embodiments, R 51 Selected from C1-C6 alkyl substituted by one or more substituents independently selected from fluorine. In some cases, R 51 is

[0252] In some embodiments, for the compound or salt of formula (I*), ring A is selected from optionally substituted 5- to 6-membered heterocycles. In some cases, the heterocycle of ring A includes at least one nitrogen atom. In some cases, the heterocycle of ring A includes at least two nitrogen atoms. In some cases, the heterocycle of ring A includes at most 1 nitrogen atom. In some cases, the heterocycle of ring A includes at most two nitrogen atoms. In some cases, ring A is substituted by one or more substituents independently selected from R 51 . In some cases, ring A is unsubstituted.

[0253] In some embodiments, for the compound or salt of formula (I*) or formula (III*), R 59 are the same. In some cases, R 59 are different. In some cases, R 59 is selected from -OH and -NH2. In some cases, R 59 is -OH.

[0254] In some embodiments, formula (I*) is represented by formula (II*) or a pharmaceutically acceptable salt thereof:

[0255]

[0256] wherein X is selected from NH, O, and S.

[0257] In some embodiments, formula (I*) is represented by formula (II-A*) or a pharmaceutically acceptable salt thereof:

[0258]

[0259] wherein R 1 is selected from O and C(R 21 )2.

[0260] In some embodiments, formula (I*) is represented by formula (II-B*) or a pharmaceutically acceptable salt thereof:

[0261]

[0262] In some embodiments, formula (I*) is represented by formula (II**) or a pharmaceutically acceptable salt thereof:

[0263]

[0264] wherein X is selected from NH, O, and S.

[0265] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 55 is selected from hydrogen, -C(O)N(H)(R 11 ), and -CH2OR 12 . In some cases, R 55 is selected from hydrogen and -C(O)N(H)(R 11 ). In some cases, R 55 is -C(O)N(H)(R 11 ). In some cases, R 55 is hydrogen. In some cases, R 11 is selected from hydrogen and C1-C3 alkyl. In some cases, R 11 is selected from C1-C3 alkyl. In some cases, R 55 is selected from hydrogen.

[0266] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 55 is -C(O)N(H)(Me). In some cases, R 55 is selected from -C(O)N(H)(Me) and -C(O)N(H2). In some cases, R 55 is -C(O)N(H2).

[0267] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 55 is -CH2OH.

[0268] For formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 12 is hydrogen.

[0269] In some embodiments, for a compound or salt of formula (II*), formula (II**), or formula (III*), X is NH.

[0270] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 52 is selected from hydrogen, halogen, and L 2 -Y 2 , where L 2 is a bond and Y 2 is a C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy.

[0271] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 52 is selected from hydrogen, halogen, CN, and L 2 -Y 2 , where L 2 is a bond and Y 2 is a C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is a C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocyclic ring. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine. In some cases, R 52 is CN.

[0272] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 52 is selected from hydrogen, halogen, -NH2, CN, -O-C 1-6 alkyl, and L 2 -Y 2 , where L 2 is a bond and Y 2 is C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocyclic ring. In some cases, R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 52 is selected from and chlorine. In some cases, R 52 is -NH2. In some cases, R 52 is selected from -O-C 1-6 alkyl. In some cases, R 52 is

[0273] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 52 is In some cases, R 52 is L 2 -Y 2 , where L 2 is -O- and Y 2 is selected from C1-C6 alkyl. In some cases, R 52 is selected from -O-CH2-CH3, hydrogen, -CN, and -NH2. In some cases, R 52 is -O-CH2-CH3. In some cases, R 52 is hydrogen. In some cases, R 52 is -CN. In some cases, R52 is -NH2. In some cases, R 52 is selected from halogen, -CN, -NH2, and L 2 -Y 2 ; wherein L 2 is selected from O and a bond, where L 2 is selected from O, Y 2 is selected from C1-C6 alkyl, and wherein when L 2 is a bond, Y 2 is selected from C2-C6 alkynyl, and the C2-C6 alkynyl is substituted by C 3-6 carbocyclic ring. In some cases, R 52 is selected from -Cl, -CN, -NH2,

[0274] In some embodiments, for the compounds or salts of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), L 2 is a bond and Y 2 is an optionally substituted 3- to 6-membered heterocycle. In some cases, Y 2 is an optionally substituted 5-membered heterocycle. In some cases, the 5-membered heterocycle is selected from each of which is optionally substituted. In some cases, the 5-membered heterocycle is optionally substituted by one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocyclic ring, and 3- to 6-membered heterocycle, where C 3-6 carbocyclic ring and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, the 5-membered heterocycle is optionally substituted by one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0275] In some embodiments, for a compound or salt of formula (I*), formula (II*), or formula (II**), the compound is selected from:

[0276] and salts of any of them.

[0277] In some embodiments, for a compound or salt of formula (I*), ring A is selected from optionally substituted C5-C6 carbocycles. In some cases, ring A is substituted with one or more substituents independently selected from R 51 .

[0278] In some embodiments, formula (I*) is represented by formula (III**) or a pharmaceutically acceptable salt thereof:

[0279]

[0280] X is selected from CH2 and NH;

[0281] m is selected from 1 and 2; and

[0282] n is selected from 0, 1, 2; and when m is 2, n is further selected from n is 3.

[0283] In some embodiments, for a compound or salt of formula (III*), the CH2 or NH of X may optionally be substituted with R 51 .

[0284] In some embodiments, for a compound or salt of formula (III*), m is 1. In some cases, m is 2.

[0285] In some embodiments, for a compound or salt of formula (III*), n is 0. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 0 or 1.

[0286] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 51 is selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group, optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R31 ) 2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

[0287] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 . In some cases, R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by one or more substituents independently selected from optionally substituted C 3-6 carbocycle substituents, wherein the C 3-6 carbocycle is optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 . In some cases, R 51 is selected from the oxo group and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from: halogen, -OR31 、 -SR 31 、 -N(R 31 )2, -C(O)R 31 、 -C(O)OR 31 、 -OC(O)R 31 、 -NO2, -CN, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 。

[0288] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 33 is selected from C 1-6 alkyl substituted by one or more substituents independently selected from: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 。 In some cases, R 33 is selected from C 1-6 alkyl substituted by a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0289] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 51 is selected from the oxo group and unsubstituted C1-C6 alkyl.

[0290] In some embodiments, for a compound or salt of formula (I*), formula (II-A*), or formula (III*), R 1 is selected from O and C(R 21 )2.

[0291] In some embodiments, for a compound or salt of formula (I*), formula (II-A*), or formula (III*), R 1 is C(R 21 )2, and R 22 and one R 21 together with the atom to which they are attached form a 3-membered carbon ring and the other R 21 is hydrogen.

[0292] In some embodiments, for a compound or salt of formula (I*), formula (II-A*), or formula (III*), R 1 is selected from O, and R 55 is selected from hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, -C(O)N(H)(R 11 ), and -CH2OR 12 . In some cases, R 1 is selected from O and R 55 is selected from -C(O)N(H)(R 11 ) and -CH2OR 12 . In some cases, R 1 is selected from O and R 55 is selected from -C(O)N(H)(R 11 ). In some cases, R 1 is selected from O and R 55 is selected from -CH2OR 12 . In some cases, R 1 is selected from O and R 55 is selected from -CH2OH.

[0293] In some embodiments, formula (I*) or formula (III*) is represented by formula (IV*) or a pharmaceutically acceptable salt thereof:

[0294]

[0295] In some embodiments, for a compound or salt of formula (I*), formula (III*), or formula (IV*), R 55 is selected from hydrogen, -C(O)N(H)(R 11 ), and -CH2OR 12 . In some cases, R 55 is -CH2OR 12 . In some cases, R 12 is hydrogen. In some cases, R55 selected from hydrogen and -C(O)N(H)(R 11 ). In some cases, R 55 is selected from -C(O)N(H)(Me) and -C(O)N(H2). In some cases, R 55 is -C(O)N(H)(Me). In some cases, R 55 is -C(O)N(H2). In some cases, R 11 is selected from hydrogen and C1-C3 alkyl. In some cases, R 11 is selected from C1-C3 alkyl. In some cases, R 55 is selected from hydrogen.

[0296] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*), or formula (IV*), R 55 is selected from -CN.

[0297] In some embodiments, for a compound or salt of formula (I*), formula (III*), or formula (IV*), X is NH.

[0298] In some embodiments, for a compound or salt of formula (I*), formula (III*), or formula (IV*), R 52 is selected from hydrogen, halogen, CN, and L 2 -Y 2 , where L 2 is a bond and Y 2 is C2-C6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, where C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In some cases, Y 2 is C2-C6 alkynyl substituted with an unsubstituted C 3-6 carbocyclic ring.

[0299] In some embodiments, for a compound or salt of formula (I*), formula (III*), or formula (IV*), R 52 is selected from L 2 -Y 2 , where L 2 is a bond and Y 2 is an optionally substituted 3- to 6-membered heterocyclic ring. In some cases, Y 2is an optionally substituted 5-membered heterocycle. In some cases, the 5-membered heterocycle is selected from each of which is optionally substituted. In some cases, the 5-membered heterocycle is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy. In some cases, the 5-membered heterocycle is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0300] In some embodiments, for a compound or salt of formula (I*), formula (III*) or formula (IV*), R 52 is selected from hydrogen and halogen. In some cases, R 52 is halogen. In some cases, R 52 is chlorine. In some cases, R 59 are the same. In some cases, R 59 are different. In some cases, R 59 is selected from -OH and -NH2. In some cases, each R 59 is -OH.

[0301] In some embodiments, for a compound or salt of formula (I*), formula (II*), formula (II-A*), formula (II-B*), formula (II**), formula (III*) or formula (IV*), R 30 , R 31 , R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6Alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 . In some cases, R 30 , R 31 , R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring. In some cases, R 30 , R 31 , R 32 and R 33 are each independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 30 is independently selected from hydrogen and C 1-6 alkyl each time it appears. In some cases, each R 31 is independently selected from hydrogen and C 1-6 alkyl each time it appears. In some cases, each R 32 is independently selected from hydrogen and C 1-6 alkyl each time it appears. In some cases, each R 33 is independently selected from hydrogen and C 1-6 alkyl each time it appears.

[0302] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the invention having sufficiently acidic functional groups, sufficiently basic functional groups, or both such functional groups can react with many inorganic bases and with any of a variety of inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having a quaternary nitrogen, can form salts with appropriate counterions (e.g., halide ions such as bromide, chloride, or fluoride ions, particularly bromide ions).

[0303] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are also intended to include all Z, E, and tautomeric forms.

[0304] "Tautomers" refer to molecules in which a proton has the potential to move from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist in tautomeric forms. Where tautomerism is possible, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0305]

[0306] In some embodiments, the compounds disclosed herein are used in different enriched isotope forms, such as in 2 H, 3 H, 11 C, 13 C, and / or 14 C are enriched. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents Nos. 5,846,514 and 6,334,997. As described in U.S. Patents Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0307] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure of the present invention, with the exception that hydrogen is replaced by deuterium or tritium, or carbon is replaced by 13 C or 14 C-enriched carbon are within the scope of this disclosure.

[0308] The compounds of the present disclosure optionally contain non-natural proportions of atomic isotopes at one or more atoms that make up such compounds. For example, the compounds can be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Labeling with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br and 125 I are all considered for isotope substitution. All isotopic variants of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0309] In certain embodiments, some or all of the 1 H atoms of the compounds disclosed herein are 2 replaced by H atoms. Methods for the synthesis of deuterium-containing compounds are known in the art and, by way of non-limiting examples only, include the following synthetic methods.

[0310] Deuterium-substituted compounds are synthesized using various methods such as those described in: Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, page 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0311] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0312] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0313] In some cases, the compounds described herein may exist as diastereoisomers, enantiomers, or other stereoisomeric forms. When the absolute stereochemistry is not specified, the compounds provided herein include all diastereoisomeric forms, enantiomeric forms, and epimeric forms, and appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography or by forming diastereoisomers and separating them by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0314] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated form as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0315] In certain embodiments, the compound or a salt of the compound may be a prodrug, for example, wherein a hydroxyl group in the parent compound is presented as an ester or a carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to cover compounds that are converted into the agents of the present disclosure under physiological conditions. One method for preparing a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal such as a specific target cell in the host animal. For example, esters or carbonates (such as esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0316] The scope of the claims includes prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the compounds as set forth herein. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0317] Prodrugs are often useful because in some cases they may be more readily administered than the parent drug. They may, for example, be made bioavailable by oral administration, whereas the parent drug may not. Relative to the parent drug, prodrugs may help enhance the cellular permeability of the compound. Prodrugs may also have improved solubility in a pharmaceutical composition compared to the parent drug. Prodrugs can be designed as reversible drug derivatives to serve as modulators for enhancing the transport of the drug to site-specific tissues or increasing the retention of the drug inside cells.

[0318] In some embodiments, the prodrug is designed to increase the lipophilicity of the agent. In some embodiments, the prodrug is designed to increase effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein by reference for this disclosure). According to another embodiment, the present disclosure provides methods for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0319] Synthetic chemical transformations and methods useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0320] C. Pharmaceutical Compositions

[0321] In certain embodiments, provided herein are compositions comprising a therapeutically effective amount of any compound or salt (also referred to herein as an “agent”) of any one of formula (I), formula (I-A), formula (I-B), formula (II), formula (II’), formula (I*), formula (II-A*), formula (II*), formula (II*), formula (II-B*), or formula (III*).

[0322] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers (including excipients and auxiliaries) that aid in processing the agent into a pharmaceutically useful formulation. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions can be found, for example, in the following: Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins, 1999).

[0323] The compositions and methods of the present disclosure can be used to treat an individual in need. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal such as a human, the composition or agent is preferably administered in the form of a pharmaceutical composition comprising, for example, the agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiological buffer saline, or other solvents or vehicles, such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used for human administration, especially for invasive routes of administration, such as routes that bypass transport or diffusion through an epithelial barrier, such as injection or implantation, the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent, or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules, granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system such as a skin patch. The composition can also be present in a solution suitable for topical administration such as eye drops.

[0324] Pharmaceutically acceptable excipients can contain, for example, physiologically acceptable agents that act to stabilize a compound such as an agent, increase the solubility of a compound such as an agent, or increase the absorption of a compound such as an agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins, or other stabilizers or excipients. The selection of pharmaceutically acceptable excipients that include physiologically acceptable agents depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be a liposome or other polymeric matrix, which can have incorporated therein, for example, the compounds of the present invention. Liposomes, for example, that contain phospholipids or other lipids are relatively simple, non-toxic, physiologically acceptable, and metabolizable carriers to prepare and administer.

[0325] A pharmaceutical composition (formulation) can be administered to a subject by any one of a number of routes of administration, including, for example, orally, such as in the form of a drench, tablet, capsule (including sprinkle capsules and gelatin capsules), bolus, powder, granule, paste for application to the tongue, as an aqueous or non-aqueous solution or suspension; by absorption through the oral mucosa, such as sublingually; rectally, per rectum or vaginally, such as in the form of a vaginal suppository, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally, in the form of, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, such as in the form of a patch for application to the skin; and topically, such as in the form of a cream, ointment or spray for application to the skin, or in the form of eye drops. The compounds can also be formulated for inhalation. In certain embodiments, the compounds can simply be dissolved or suspended in sterile water.

[0326] The pharmaceutical composition can be a sterile aqueous or non-aqueous solution, suspension or emulsion, such as a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to the amount of one or more agents that, when administered to a subject as a single dose or as part of a series of doses, is effective in producing the desired therapeutic effect.

[0327] The therapeutic efficacy of a subject can generally be monitored using assays and methods suitable for the condition being treated, which assays will be familiar to those of ordinary skill in the art and are described herein. The pharmacokinetics of the agent or one or more of its metabolites administered to the subject can be monitored by determining the level of the agent or metabolite in a biological fluid, such as blood, a blood fraction such as serum, and / or urine and / or other biological samples or biological tissues from the subject. Any method of detecting an agent practiced in the art and described herein can be used to measure the level of the agent or metabolite during the course of treatment.

[0328] The dosage of the pharmaceutical agent described herein for treating a disease or disorder can depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the overall health status, as well as age, gender, and weight, and other factors that will be apparent to those skilled in the medical arts. The pharmaceutical composition can be administered in a manner suitable for the disease to be treated as determined by those skilled in the medical arts. In addition to the factors described herein and above related to the use of the pharmaceutical agent to treat a disease or disorder, the suitable duration and frequency of administration of the pharmaceutical agent can also be determined or adjusted based on factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the agent can generally be determined using experimental models and / or clinical trials. The optimal dosage can depend on the body mass, weight, or blood volume of the subject. It is generally preferred to use the minimum dosage sufficient to provide effective treatment. The design and conduct of preclinical and clinical studies of the pharmaceutical agent described herein (including when administered to obtain a prophylactic benefit) are entirely within the skill of those skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dosage of each agent can be different, such as less than when either agent is administered alone as a single-agent therapy. In certain specific embodiments, the two pharmaceutical agents in combination can act synergistically or additively, and either agent can be used in an amount less than when administered alone. The amount of the pharmaceutical agent that can be administered daily can be, for example, between about 0.01 mg / kg and 100 mg / kg, such as between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10 - 50 mg / kg, between about 50 - 100 mg / kg body weight. In other embodiments, the amount of the pharmaceutical agent that can be administered daily is between about 0.01 mg / kg and 1000 mg / kg, between about 100 - 500 mg / kg, or between about 500 - 1000 mg / kg body weight. The optimal dosage per day or per course of treatment can be different for the disease or disorder to be treated and can also vary with the route of administration and the treatment regimen.

[0329] The pharmaceutical composition comprising the pharmaceutical agent can be formulated in a manner suitable for the delivery method using techniques conventionally practiced in the art. The composition can be in the form of a solid (e.g., tablets, capsules), semi-solid (e.g., gels), liquid, or gas (e.g., aerosols). In other embodiments, the pharmaceutical composition is administered in a bolus infusion form.

[0330] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilizates. The compositions described herein may be lyophilized or otherwise formulated as a lyophilized product, and upon administration, the medicament is dissolved and / or diluted with a solution of one or more suitable excipients. In other embodiments, the medicament may be encapsulated within liposomes using techniques known and practiced in the art. In certain specific embodiments, the medicament is not formulated within liposomes for delivery to a stent for treating a highly but not completely occluded artery. The pharmaceutical composition may be formulated for any suitable mode of administration described herein and in the art.

[0331] For example, pharmaceutical compositions for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods may be in liquid form. Liquid pharmaceutical compositions may include, for example, one or more of the following: sterile diluents such as water, saline solutions (preferably physiological saline), Ringer's solution, isotonic sodium chloride, non-volatile oils that may act as solvents or suspending media, polyethylene glycol, glycerol, propylene glycol, or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral compositions may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. The use of physiological saline is preferred, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for treating ophthalmic conditions or diseases, the liquid pharmaceutical composition may be administered to the eye in the form of eye drops. The liquid pharmaceutical composition may be delivered orally.

[0332] For oral formulations, at least one of the agents described herein can be used alone or in combination with suitable additives to prepare tablets, powders, granules, or capsules, and, if desired, in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavorants. The agent can be formulated with a buffer to provide protection of the compound from the low pH of the gastric environment, and / or formulated with an enteric coating. The agent included in the pharmaceutical composition can be formulated with a flavorant, for example, in liquid, solid, or semi-solid dosage forms, and / or formulated with an enteric coating for oral delivery.

[0333] A pharmaceutical composition comprising any of the agents described herein can be formulated for sustained or slow release, also known as timed release or controlled release. Such compositions can generally be prepared using well-known techniques and administered, for example, orally, rectally, intradermally, or subcutaneously by implantation, or by implantation at the desired target site. Sustained release formulations can contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use in such formulations are biocompatible and can also be biodegradable; preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of the agent contained in the sustained release formulation depends on the site of implantation, the rate of release and the expected duration, as well as the nature of the condition, disease, or disorder to be treated or prevented.

[0334] In certain embodiments, a pharmaceutical composition comprising the agent is formulated for transdermal, intradermal, or topical administration. The composition can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, in the form of a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This is preferably in the form of a controlled release formulation or a sustained release formulation, which is topically administered or directly injected, for example, intradermally or subcutaneously, into the skin adjacent to or within the area to be treated. The active composition can also be delivered by iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenethyl alcohol, thimerosal, and combinations thereof.

[0335] A pharmaceutical composition containing a medicament can be formulated as an emulsion for topical application. The emulsion contains a liquid that is distributed in the bulk of a second liquid. The emulsion can be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the water phase can contain one or more surfactants, emulsifying agents, emulsion stabilizers, buffering agents, and other excipients. The oil phase can contain other pharmaceutically approved oily excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. The composition for topical application can also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0336] Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. Lotions can be formulated with an aqueous or oily base and generally will also contain one or more emulsifying agents, stabilizers, dispersing agents, suspending agents, thickeners, or coloring agents. Liquid sprays can be delivered from a pressurized package, for example, through a specially shaped closure. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsion, microemulsion, or foam emulsion systems.

[0337] In some embodiments, the medicaments described herein can be formulated as inhalants. The inhalation method can deliver the drug directly to the airways. The medicaments can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The medicaments can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery in the form of a liquid aerosol or an inhalable dry powder. The liquid aerosol formulation is optionally atomized primarily to a particle size that can be delivered to the terminal and respiratory bronchioles. The liquid aerosol and inhalable dry powder formulations preferably deliver throughout the bronchial tree to the terminal bronchioles and ultimately to the parenchymal tissue.

[0338] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device such as a nebulizer, vibrating perforated plate, or ultrasonic nebulizer, which is preferably selected to allow the formation of aerosol particles having a mass median aerodynamic diameter primarily between 1 and 5 μm. Additionally, the formulation preferably has an isotonic ionic strength and chloride concentration, and a minimum aerosolizable volume capable of delivering an effective dose of the medicament. Further, the aerosolized formulation preferably does not adversely impair the functionality of the airways and does not cause undesirable side effects.

[0339] A nebulizing device suitable for administering the aerosol formulations described herein includes, for example, jet nebulizers, vibrating perforated plates, ultrasonic nebulizers, and electrically powered dry powder inhalers, which are capable of nebulizing the formulation into an aerosol particle size predominantly in the range of 1-5 μm. In the present application, predominantly means that at least 70% but preferably more than 90% of all the aerosol particles produced are in the range of 1-5 μm. Jet nebulizers operate by air pressure to break up a liquid solution into aerosol droplets. Vibrating perforated plate nebulizers operate by using acoustic vacuums generated by a rapidly vibrating perforated plate to extrude solvent droplets through the perforated plate. Ultrasonic nebulizers operate by piezoelectric crystals that shear a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, the AeroNebTM and AeroDoseTM vibrating perforated plate nebulizers (AeroGen, Inc., Sunnyvale, California), nebulizers (Medic-Aid Ltd., West Sussex, England), Pari and Pari LC jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia) and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0340] In some embodiments, the medicament can be formulated with an oily matrix or an ointment to form a semi-solid composition having a desired shape. In addition to the medicament, these semi-solid compositions can also contain dissolved and / or suspended bactericides, preservatives, and / or buffer systems. The petrolatum component that can be included can be any paraffin wax that ranges in viscosity from mineral oil admixed with isobutene, colloidal silica, or stearate to solid paraffin wax. Absorbent matrices can be used with the oily system. Additives can include cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, lanolin alcohols, low HLB (hydrophobic-lipophilic balance) emulsifiers, and a variety of ionic and non-ionic surfactants, either alone or in combination.

[0341] Controlled or sustained release of transdermal or topical formulations can be achieved by adding timed release additives available in the art such as polymeric structures, matrices. For example, the composition can be administered by using hot melt extrusion products such as bioadhesive hot melt extrusion films. The formulation can comprise a crosslinked polycarboxylic acid polymer formulation. The crosslinking agent can be present in an amount that provides sufficient adhesion to allow the system to remain attached to the target epithelial or endothelial cell surface for a sufficient time to allow for the desired release of the compound to be achieved.

[0342] Inserts, transdermal patches, bandages or articles can comprise a mixture or coating of polymers that provide release of a medicament at a constant rate over an extended period. In some embodiments, the article, transdermal patch or insert comprises a water-soluble pore former, such as polyethylene glycol (PEG), that can be mixed with a water-insoluble polymer to increase the persistence of the insert and extend the release of the active ingredient.

[0343] Transdermal devices (inserts, patches, bandages) can also comprise water-insoluble polymers. Rate controlling polymers can be used to administer to sites where pH changes can be used to effect release. These rate controlling polymers can be applied using a continuous film coating during the process of spraying and drying with the active compound. In one embodiment, a coating formulation is used to coat pellets comprising the active ingredient, which are pressed to form a solid biodegradable insert.

[0344] Polymeric formulations can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained release gels and compounds can be incorporated into a polymeric matrix such as a hydrophobic polymeric matrix. Examples of polymeric matrices include microparticles. The microparticles can be microspheres and the core can have a material different from the polymeric shell. Alternatively, the polymer can be cast into thin sheets or films, powders produced by milling or other standard techniques, or gels such as hydrogels. The polymer can also be in the form of a coating or part of a bandage, scaffold, catheter, vascular graft or other device to facilitate delivery of the medicament. The matrix can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0345] Kits are provided having unit doses of one or more of the medicaments described herein, the unit doses typically in oral or injectable dosage forms. Such kits can include a container containing the unit dose, an information package insert describing the use of the drug in treating a disease and the attendant benefits, and optionally an appliance or device for delivering the composition.

[0346] D. Methods of Treatment

[0347] The compounds described herein (e.g., of formula (I), formula (I-A), formula (I-B), formula (II), formula (II’), formula (I*), formula (II-A*), formula (II*), formula (II*), formula (II-B*) or formula (III*)) can be used to prepare a medicament for preventing or treating a disease or condition. In addition, a method for treating any disease or condition described herein in a subject in need of such treatment involves administering to the subject a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0348] Compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the composition is administered to a patient who has contracted the disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The amount effective for this purpose will depend on the severity and course of the disease or condition; previous therapy; the health status, weight, and response of the patient to the drug; and the judgment of the treating physician.

[0349] In prophylactic applications, the composition containing the compounds described herein is administered to a patient susceptible to a particular disease, disorder, or condition or otherwise at risk of a particular disease, disorder, or condition. Such amount is defined as a "prophylactically effective amount or dose". In such case, the exact amount also depends on the health status, weight, etc. of the patient. When used in a patient, the effective amount for this purpose will depend on the severity and course of the disease, disorder, or condition; previous therapy; the health status and response of the patient to the drug; and the judgment of the treating physician.

[0350] In cases where the condition of the patient does not improve, after the judgment of the doctor, the administration of the compound can be carried out for a long time, that is, for a continuously extended period, including throughout the entire duration of the patient's life, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0351] Once the condition of the patient has improved, a maintenance dose is administered if necessary. Subsequently, the dose administered or the frequency of administration or both can be reduced as the symptoms vary to maintain the improved disease, disorder, or condition. However, after any recurrence of the symptoms, the patient may require long-term intermittent treatment.

[0352] The amount of the given agent corresponding to such amount will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity (e.g., weight) of the subject or host to be treated, yet can be determined in a manner recognized in the art according to the specific circumstances surrounding the case, which include, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated. Generally, however, the dosage for adult treatment will typically be in the range of about 0.02 mg to about 5000 mg per day, and in some embodiments, about 1 mg to about 1500 mg per day. The required dosage can be conveniently provided as a single dose or as divided doses, which are administered simultaneously (or within a short period) or at appropriate intervals, for example, in the form of two, three, four or more sub-doses per day.

[0353] The pharmaceutical compositions described herein can be in unit dosage forms suitable for precise single administration. In a unit dosage form, the preparation is divided into unit doses containing a suitable amount of one or more compounds. The unit dose can be in the form of a package containing discrete dosage amounts. Non-limiting examples are packages of tablets or capsules and powders in vials or ampoules. An aqueous suspension composition can be packaged in a single-dose non-reclosable container. Alternatively, a multi-dose reclosable container can be used, in which case, typically, a preservative is included in the composition. By way of example only, a preparation for parenteral injection can be provided in a unit dosage form, which includes, but is not limited to, ampoules, or in a multi-dose container with the addition of a preservative.

[0354] The toxicity and therapeutic efficacy of such treatment regimens can be determined in cell cultures or experimental animals by standard pharmaceutical procedures, including but not limited to determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio between LD 50 and ED 50 . Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is preferably within the range of circulating concentrations that include the ED 50 with minimal toxicity. Depending on the dosage form employed and the route of administration utilized, the dosage can vary within this range.

[0355] In certain embodiments, the present invention provides a method for treating or preventing a disease, condition or disorder selected from vascular inflammation, arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia, cerebral palsy, chronic hypoxia attributable to arteriovenous malformation and occlusive cerebral arterial disease, ischemia and reperfusion injury in skeletal muscle, severe neurological disorders associated with excitotoxicity, Parkinson's disease, Huntington's disease, CNS diseases, heart diseases, kidney diseases, glaucoma, cancer, neuropathic pain, transient ischemic attack, bone marrow protection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis and septic shock. In some cases, the disease, condition or disorder is neuropathic pain. In some cases, the disease, condition or disorder is selected from chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, neurodegeneration, drug-induced ototoxicity, spinocerebellar degeneration, symptoms associated with traumatic brain injury, chemotherapy-induced cognitive impairment, pain and discomfort of irritable bowel syndrome, and neuropathic pain.

[0356] In certain embodiments, the present invention provides a method for treating or preventing a disease, condition or disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of the embodiments of the present invention. The disease, condition or disorder may be selected from neuropathic pain, vascular inflammation, arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia, cerebral palsy, chronic hypoxia attributable to arteriovenous malformation and occlusive cerebral arterial disease, ischemia and reperfusion injury in skeletal muscle, severe neurological disorders associated with excitotoxicity, Parkinson's disease, Huntington's disease, CNS diseases, heart diseases, kidney diseases, glaucoma, cancer, neuropathic pain, diabetic-related neuropathic pain, transient ischemic attack, bone marrow protection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis and septic shock. In a preferred embodiment, the present invention provides a method for treating or preventing neuropathic pain in a patient in need thereof. In another preferred embodiment, the present invention provides a method for treating or preventing postoperative pain in a patient in need thereof.

[0357] In certain embodiments, the present disclosure provides a method of treating a condition selected from the group consisting of chronic inflammatory conditions, chronic neuropathic pain and mixed pain conditions, neurodegenerative conditions, cognitive impairment conditions, unwanted side effects of opioid analgesic therapy, congestive heart failure, myocarditis, giant cell arteritis, temporal arteritis, aortic (Takayasu's) arteritis, vasculitis, atherosclerotic vascular lesions, chronic bronchitis, chronic pancreatitis, hepatic steatohepatitis (including alcoholic and non-alcoholic types), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), inflammatory bowel syndrome, cholangitis, cholecystitis, interstitial cystitis, duodenitis, lymphadenitis, prostatitis, salpingitis, arthritis (including osteoarthritis and rheumatoid arthritis), temporomandibular joint dysfunction, myositis (including polymyositis and dermatomyositis), osteitis (including periostitis and osteomyelitis), macular degeneration (wet and dry types), glaucoma, uveitis, iritis, dry eye syndrome, and ototoxicity (deafness, hyperacusis, and vestibular dysfunction) induced by drugs (including but not limited to platinum-containing chemotherapeutic agents, aminoglycoside antibiotics, and loop diuretics) and noise, trigeminal neuralgia, post-traumatic painful neuropathy (causalgia and complex regional pain syndrome), post-herpetic neuralgia, diabetic neuropathy, small fiber neuropathy, burning mouth syndrome (glossodynia), vulvodynia (including vulvar vestibulitis), chemotherapy-induced peripheral neuropathy (including but not limited to neuropathy caused by chemotherapeutic agents of the vinca alkaloid class, taxane class, platinum class, and proteasome inhibitor class), spinal cord injury pain, chronic low back pain, chronic neck pain, sciatica, discogenic pain, fibromyalgia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Leber's optic neuropathy, frontotemporal dementia, dementia with Lewy bodies (DLB), spinocerebellar degeneration, multiple sclerosis, diabetic neuropathy, small fiber neuropathy, chemotherapy-induced neuropathy, traumatic brain injury (including concussion), postoperative cognitive dysfunction, chemotherapy-induced or radiation-induced damage to oral and gastrointestinal mucosa (mucositis), hepatocellular carcinoma, adverse effects attributable to anticancer drugs, overactive bladder, pelvic pain, prostatodynia, interstitial cystitis, septic shock, erectile dysfunction, acne, dynamic wrinkles, and psoriasis.

[0358] In certain embodiments, the present disclosure provides a method of treating a condition selected from chronic inflammatory conditions, chronic neuropathic pain and mixed pain conditions, neurodegenerative conditions, cognitive impairment conditions, unwanted side effects of opioid analgesic therapy, congestive heart failure, myocarditis, giant cell arteritis, temporal arteritis, aortic (Takayasu's) arteritis, vasculitis, atherosclerotic vascular lesions, chronic bronchitis, chronic pancreatitis, hepatic steatohepatitis (including alcoholic and non-alcoholic types), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), inflammatory bowel syndrome, cholangitis, cholecystitis, interstitial cystitis, duodenitis, lymphadenitis, prostatitis, salpingitis, arthritis (including osteoarthritis and rheumatoid arthritis), temporomandibular joint dysfunction, myositis (including polymyositis and dermatomyositis), osteitis (including periostitis and osteomyelitis), macular degeneration (wet and dry types), glaucoma, uveitis, iritis, dry eye syndrome, and ototoxicity (deafness, hyperacusis, and vestibular dysfunction) induced by drugs (including but not limited to platinum-containing chemotherapeutic agents, aminoglycoside antibiotics, and loop diuretics) and noise, trigeminal neuralgia, post-traumatic painful neuropathy (causalgia and complex regional pain syndrome), post-herpetic neuralgia, diabetic neuropathy, small fiber neuropathy, burning mouth syndrome (glossodynia), vulvodynia (including vulvar vestibulitis), chemotherapy-induced peripheral neuropathy (including but not limited to neuropathy caused by chemotherapeutic agents of the vinca alkaloid class, taxane class, platinum class, and proteasome inhibitor class), spinal cord injury pain, chronic low back pain, chronic neck pain, sciatica, discogenic pain, fibromyalgia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Leber's hereditary optic neuropathy, frontotemporal dementia, dementia with Lewy bodies (DLB), spinocerebellar degeneration, multiple sclerosis, diabetic neuropathy, small fiber neuropathy, chemotherapy-induced neuropathy, traumatic brain injury (including concussion), postoperative cognitive dysfunction, chemotherapy-induced or radiation-induced damage to oral and gastrointestinal mucosa (mucositis), hepatocellular carcinoma, adverse effects attributable to anticancer drugs, overactive bladder, pelvic pain, prostatodynia, interstitial cystitis, septic shock, erectile dysfunction, acne, dynamic wrinkles, and psoriasis.

[0359] In certain embodiments, the present disclosure provides a method of treating a condition selected from hyperkinesia, hypertension, acute hypoxia, depression, and infertility.

[0360] In certain embodiments, the present disclosure provides a method of treating a condition selected from inflammatory conditions such as vascular inflammation and arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia (cerebral palsy; prophylactic treatment involves long-term exposure via the placental circulation), chronic hypoxia attributable to arteriovenous malformations and occlusive cerebral arterial disease, ischemia and reperfusion injury in skeletal muscle, severe neurological conditions associated with excitotoxicity, Parkinson's disease, Huntington's disease, and other CNS diseases, heart disease, kidney disease, and contraception.

[0361] In certain embodiments, the compounds of the present invention can also be used to treat pain associated with chemotherapy-induced peripheral neuropathy (CIPN), which is induced by one or more combinations comprising chemotherapeutic drugs as part of a treatment regimen. Non-limiting examples of the combinations include CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone, and procarbazine); CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); COP (cyclophosphamide, vincristine, and prednisone); CAP-BOP (cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone); m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin); ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, mechloethamine, vincristine, prednisone, and procarbazine); ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin, cytarabine, bleomycin, and vincristine); MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin); MOPP (mechloethamine, vincristine, prednisone, and procarbazine); ABVD (adriamycin / doxorubicin, bleomycin, vinblastine, and dacarbazine); MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABV (adriamycin / doxorubicin, bleomycin, and vinblastine); MOPP (mechloethamine, vincristine, prednisone, and procarbazine) alternating with ABVD (adriamycin / doxorubicin, bleomycin, vinblastine, and dacarbazine); ChIVPP (chlorambucil, vinblastine, procarbazine, and prednisone); IMVP-16 (ifosfamide, methotrexate, and etoposide); MIME (methyl-gag, ifosfamide, methotrexate, and etoposide); DHAP (dexamethasone, high-dose cytaribine, and cisplatin); ESHAP (etoposide, methylpredisolone, high-dose cytaribine, and cisplatin);CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin); CAMP (lomustine, mitoxantrone, cytarabine, and prednisone); CVP-1 (cyclophosphamide, vincristine, and prednisone), ESHOP (etoposide, methylprednisolone, high-dose cytarabine, vincristine, and cisplatin); EPOCH (etoposide, vincristine, and doxorubicin for 96 hours, and bolus doses of cyclophosphamide and oral prednisone), ICE (ifosfamide, cyclophosphamide, and etoposide), CEPP(B) (cyclophosphamide, etoposide, procarbazine, prednisone, and bleomycin), CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), CEPP-B (cyclophosphamide, etoposide, procarbazine, and bleomycin), and P / DOCE (epirubicin or doxorubicin, vincristine, cyclophosphamide, and prednisone).;

[0362] In certain embodiments, the method comprises administering to a subject a combination of a first amount of a compound or salt described herein and a second amount of an analgesic, wherein the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both may be less than the effective amount of each compound administered as monotherapy. The therapeutically effective amount of the compound and the analgesic of the present invention may be administered to the subject simultaneously or separately in any given order and by the same or different routes of administration. It may be advantageous to initiate administration of the compound of the present invention first, for example, one or more days or one or more weeks before initiating administration of the analgesic. Additionally, additional drugs may be administered in combination with the above combination therapy. In certain embodiments, the present disclosure provides a method of treating or preventing chemotherapy-induced peripheral neuropathy (CIPN) in a subject, the method comprising administering to the subject a compound, salt, or pharmaceutical composition described herein. In some embodiments, the CIPN is attributed to anticancer chemotherapy. In some cases, the anticancer chemotherapy is a taxane chemotherapeutic agent, a platinum complex chemotherapeutic agent, a vinca alkaloid chemotherapeutic agent, or a proteasome inhibitor chemotherapeutic agent. In some cases, the CIPN is attributed to antiviral chemotherapy. In some cases, the antiviral chemotherapy is anti-HIV chemotherapy.

[0363] In certain embodiments, the present disclosure provides a method of treating or preventing diabetic peripheral neuropathy in a subject, the method comprising administering to the subject a compound, salt, or pharmaceutical composition as described herein.

[0364] In certain embodiments, the present disclosure provides a method of treating or preventing neurodegeneration in a subject, the method comprising administering to the subject a compound, salt, or pharmaceutical composition as described herein. In some cases, the neurodegeneration is attributed to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or Leber's hereditary optic neuropathy.

[0365] In certain embodiments, the present disclosure provides a method of preventing or treating drug-induced ototoxicity in a subject, the method comprising administering to the subject a compound, salt, or pharmaceutical composition as described herein. In some embodiments, the drug-induced ototoxicity is deafness, tinnitus, or hyperacusis.

[0366] In certain embodiments, the present disclosure provides a method of treating or preventing spinocerebellar degeneration in a subject, the method comprising administering to the subject a compound, salt, or pharmaceutical composition as described herein.

[0367] In certain embodiments, the present disclosure provides a method for treating or preventing symptoms associated with traumatic brain injury in a subject in need thereof, the method comprising administering to the subject a compound, salt, or pharmaceutical composition as described herein. In some cases, the method comprises treating one or more symptoms associated with traumatic brain injury. In some cases, the one or more symptoms are cognitive impairments. In some cases, the cognitive impairment comprises at least one of the following: memory loss; disruption of insight, judgment, and thinking; reduced processing speed; distractibility and / or deficits in executive functions (such as abstract reasoning, planning, problem-solving, and multitasking). In some cases, the compound, salt, or pharmaceutical composition is administered within 24 hours or within 48 hours of the traumatic brain injury. In some cases, the compound, salt, or pharmaceutical composition is administered in multiple doses.

[0368] In certain embodiments, the present disclosure provides a method for treating or preventing chemotherapy-induced cognitive impairment, the method comprising administering a compound, salt, or pharmaceutical composition described herein to a patient who is undergoing or will undergo cancer chemotherapy treatment. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition prior to cancer chemotherapy treatment. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition from about one minute to about 7 days prior to cancer chemotherapy treatment. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition concurrently with cancer chemotherapy treatment. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition only on the days of administration of cancer chemotherapy treatment. In some embodiments, the method comprises administering the compound, salt, or pharmaceutical composition on the days of administration of cancer chemotherapy treatment and on one or more of those days that are between successive doses of the chemotherapeutic agent. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition after cancer chemotherapy treatment. In some cases, the method comprises administering the compound, salt, or pharmaceutical composition from about one minute to about 7 days after cancer chemotherapy treatment. In some cases, the cancer chemotherapy treatment is selected from taxane agents, platinum complex agents, vinca alkaloids, proteasome inhibitors, 5-fluorouracil, methotrexate, doxorubicin, and combinations thereof.

[0369] In certain embodiments, the present disclosure provides a method for treating or preventing SARS-COV2-induced cognitive impairment, the method comprising administering a compound, salt, or pharmaceutical composition described herein to a patient. The compound is administered once the patient has received a positive test for COVID infection. Cognitive impairment has been associated with neuroinflammation involving microglia (Fernandez-Castenada et al., Cell 185:2452 (2022)) and A3 adenosine receptor agonists reduce cytokine release from microglia.

[0370] In certain embodiments, the present disclosure provides a method for treating pain and discomfort associated with irritable bowel syndrome, the method comprising administering a compound, salt, or pharmaceutical composition described herein to a patient who is undergoing or will undergo cancer chemotherapy treatment. In some cases, the method comprises administering prior to the onset of pain or discomfort. In some cases, the method comprises administering after the onset of pain or discomfort. In some cases, the method comprises administering during the onset of pain or discomfort. In some cases, the pain or discomfort is reduced by at least about 10%, as determined by measuring the abdominal response to colorectal distension. In some cases, the pain or discomfort is reduced by at least about 50%. In some cases, the pain or discomfort is reduced by at least about 90%. In some cases, the pain or discomfort is reduced by at least about 10%, as determined by measuring the visceromotor response to colorectal distension. In some cases, the pain or discomfort is reduced by at least 50%. In some cases, the pain or discomfort is reduced by at least 90%. In some cases, the administration is performed at least 5 days after the onset of pain or discomfort.

[0371] In certain embodiments, regardless of the cause of the pain, the compounds or salts of the present disclosure administered in combination with an analgesic can be used to alleviate the symptoms of neuropathic pain, the causes of which include, but are not limited to, spinal cord injury, multiple sclerosis, stroke, diabetes, herpes zoster infection, HIV-related neuropathy, nutritional deficiencies, toxins, distal manifestations of malignancies, hereditary immune-mediated disorders, or physical trauma to the nerve trunk, cancer, chemotherapy, radiation injury, or surgery (e.g., postoperative pain), vulvodynia, and burning mouth syndrome. In one embodiment, the neuropathic pain is associated with long-term opioid use.

[0372] In certain embodiments, A3AR antagonists are suitable for treating renal fibrosis or glaucoma and other conditions resulting from abnormally high activation of A3AR.

[0373] The analgesic administered in combination with the compounds of the present invention can be selected based on the particular condition being treated. Currently known analgesics include, but are not limited to, opioids, morphine mimetics, antidepressants, antiepileptics, NMDA receptor antagonists, fatty acid amide hydrolase inhibitors, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, NOS inhibitors, acetaminophen, and calcium channel subunit α2δ ligands.

[0374] Exemplary opioids include any natural or synthetic opioid analgesics such as morphine, fentanyl, codeine, thebaine, diacetylmorphine (heroin), dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone, oxymorphone, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl, nocaine, pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodine, PEPAP, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, levoalphacetylmethadol (LAAM), loperamide, diphenoxylate, pentazocine, phenazocine, buprenorphine, etorphine, butorphanol, nalbuphine, levorphanol, levomethorphan, dezocine, lefetamine, tilidine, tramadol, propoxyphene, and oxycodone. As contemplated herein, opioids also encompass any natural or synthetic narcotic antagonists such as nalmefene, naloxone, or naltrexone, and any natural or synthetic mixed opioid agonist / antagonists such as nalbuphine, butorphanol, buprenorphine, and pentazocine.

[0375] Exemplary non-steroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen, acetaminophen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tofenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, and licofelone.Exemplary antidepressants include tricyclic antidepressants such as: amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, and quinupramine; amineptine, norepinephrine, iprindole, opipramol, tianeptine, trimipramine, carbamezapine, and flupirtine.

[0376] It is contemplated that the compounds or salts of the present invention may be particularly suitable for treating pain when co-administered with an opioid, a tricyclic antidepressant, or an analgesic agent that is believed to bind to the α2δ subunit of a calcium channel, i.e., a calcium channel α2δ ligand. Examples of such ligands include GABA analogs such as gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid) and pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid).

[0377] In certain embodiments, the method comprises administering to a subject a combination of a first amount of a compound or salt described herein and a second amount of a dopamine agonist such as carbidopa or levodopa.

[0378] The relative amounts of the optional compound or its salt are provided to afford synergistic pain relief. For example, suitable ratios of the compounds of the invention to gabapentin can range from about 0.1 part by weight of the compound to about 3 to about 30 parts by weight of gabapentin. Suitable ratios of the compounds of the invention to morphine can range from about 0.1 part by weight of the compound to about 1 to about 5 parts by weight of morphine. Although these ratios are calculated with respect to the free compound (non-salt form), it will be appreciated that equivalent ratios of the pharmaceutically acceptable salts or prodrugs of the compounds can be readily determined by using the ratios of the molecular weights of the salts.

[0379] In certain embodiments, co-administration of a compound of the invention and an analgesic is achieved by formulating the compounds together in a combination composition. The combination composition can comprise a first pharmaceutically acceptable composition containing a first amount of a compound of the invention and a second pharmaceutically acceptable composition comprising a second amount of the analgesic, wherein the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both can be less than the effective amount of each compound administered as monotherapy. The combination composition is a pharmaceutically acceptable composition comprising a first amount of a compound or salt of the invention and a second amount of the analgesic, wherein the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both can be less than the effective amount of each compound administered as monotherapy.

[0380] In one embodiment, the invention provides a method of reducing opioid antinociceptive tolerance and / or hypersensitivity in a subject receiving opioid therapy, the method comprising administering to the subject an amount of a compound or salt of the invention sufficient to reduce opioid antinociceptive tolerance.

[0381] In another embodiment, a method of preventing or treating opioid dependence i.e., withdrawal in a subject receiving an opioid preparation is provided, the method comprising administering to the subject an amount of a compound or salt of the invention sufficient to treat one or more symptoms of opioid withdrawal. The opioid can be morphine, oxycodone, fentanyl, cocaine, heroin, or opium. The compound or salt of the invention can be delivered before the onset of withdrawal or after the onset of withdrawal. The compound or salt of the invention can be co-administered with a decreasing dose of the opioid. The compound or salt of the invention can be delivered before the onset of opioid therapy. The compound or salt of the invention can be delivered for a period of time after opioid is no longer administered to the subject. The compound or salt of the invention can be delivered for a period of one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, or six months after opioid is no longer administered to the subject. The opioid and / or the compound or salt of the invention can be delivered by continuous infusion such as by an implanted pump.

[0382] One or more symptoms of opioid withdrawal can include agitation, anxiety, muscle pain, increased tearing, insomnia, rhinorrhea, sweating, and yawning, while late symptoms of withdrawal include abdominal cramps, diarrhea, dilated pupils, goose bumps, nausea, and / or vomiting. The method can also include subjecting the subject to a drug treatment program, such as methadone treatment or buprenorphine treatment.

[0383] In other embodiments, the compounds or salts of the invention are administered in combination with agents such as: TNF-α inhibitors, IL-1β inhibitors, p38 kinase inhibitors, ERK inhibitors, JNK inhibitors, regulators of transcription factors such as NF-κB, agents that modulate glial cell function, agents that block the expression and / or activity of adenosine kinase, recombinant ectonucleotidases, ENT inhibitors, and the like. Non-limiting examples of p38 kinase inhibitors include PH-797804, BIRB 796, VX-702, SB 239063, SB202190, SCIO 469, and BMS 582949. An example of an ERK inhibitor is sorafenib. An example of a JNK inhibitor is AM-111. Non-limiting examples of NF-κB regulators include disulfiram, olmesartan, dithiocarbamate, and anatabine.

[0384] The following examples further illustrate the invention, but should not of course be construed as limiting its scope in any way.

[0385] Examples

[0386] The invention, which has been generally described above, will be more readily understood by reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0387] The following synthetic schemes are provided for illustrative purposes only. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to carry out the preparation in a similar manner as described below by using appropriate starting materials and modifying the synthetic route as needed. Generally, the starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0388] Abbreviations: ACN acetonitrile; BSA bis(trimethylsilyl)acetamide; DCM dichloromethane; DHP 3,4-dihydropyran; DIAD diisopropyl azodicarboxylate; DIPEAN, N-diisopropylethylamine; DMSO dimethyl sulfoxide; EA ethyl acetate; HMPA hexamethylphosphoramide; IBX 2-iodoxybenzoic acid; LDA lithium diisopropylamide; NMP N-methyl-2-pyrrolidone; PE petroleum ether; PTSA p-toluenesulfonic acid; TEA triethylamine; TFA trifluoroacetic acid; THF tetrahydrofuran; TiPSCl triisopropylchlorosilane; T3P propanephosphonic acid; and XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

[0389] Monitor all reactions by thin layer chromatography (TLC) or by LCMS or by HPLC. Perform chromatography by silica gel column chromatography using the listed solvents.

[0390] Example 1: Synthesis of 14B

[0391]

[0392] General procedure for the preparation of compound 3

[0393]

[0394] Under N2, add PPh3 (34.6 g, 131.91 mmol, 2.0 equiv) and DIAD (26.67 g, 131.91 mmol, 25.65 mL, 2.0 equiv) to a solution of compound 1 (35.0 g, 79.09 mmol, 1.2 equiv) in THF (440 mL). Stir the mixture at 20 °C for 15 min. Then add compound 2 (12.4 g, 65.96 mmol, 1.0 equiv) to the mixture and stir at 20 °C for 16 h. LCMS shows the reaction is complete. Concentrate the mixture under reduced pressure to give a residue, which is purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to afford compound 3 (61.0 g, crude) as a yellow solid. LCMS of the reaction mixture: Rt = 0.930, MS: 612.1 (M+H) + 。 11H NMR: 400 MHz DMSO-d6 δ (ppm) 8.68 (s, 1H), 7.62 (s, 1H), 7.38 - 7.24 (m, 15H), 5.24 (d, J = 7.2 Hz, 1H), 5.05 (s, 1H), 4.79 (d, J = 7.2 Hz, 1H), 3.38 - 3.28 (m, 2H), 1.75 - 1.72 (m, 1H), 1.46 (s, 3H), 1.19 (s, 3H), 1.03 (t, J = 4.8 Hz, 1H), 0.95 - 0.93 (m, 1H).

[0395] General procedure for the preparation of Compound 4

[0396]

[0397] At 30 °C, AcOH (8.53 mol, 610 mL, 80% purity, 85.7 equiv) was added to a solution of Compound 3 (61.0 g, crude) in ACN (160 mL). The mixture was stirred at 30 °C for 16 h. TLC (petroleum ether:ethyl acetate = 1:1) showed the completion of the reaction. The reaction mixture was basified with NH3·H2O to adjust the pH to 8, followed by extraction with ethyl acetate (400 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 1:3) to afford Compound 4 as a yellow solid (13.3 g, 36.0% yield). LCMS of the reaction mixture: Rt = 0.725, MS: 370.1 (M + H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.75 (s, 1H), 7.67 (s, 1H), 5.20 (d, J = 7.2 Hz, 1H), 5.01 (s, 1H), 4.95 (t, J = 5.2 Hz, 1H), 4.66 - 4.65 (m, 2H), 3.47 - 3.43 (m, 1H), 1.72 - 1.69 (m, 1H), 1.45 (s, 3H), 1.16 (s, 3H), 1.00 - 0.92 (m, 2H).

[0398] General procedure for the preparation of Compound 5

[0399]

[0400] At 20 °C, IBX (11.1 g, 39.68 mmol, 1.3 equiv) was added to a solution of compound 4 (11.3 g, 30.52 mmol, 1.0 equiv) in ACN (115 mL). The mixture was stirred at 80 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The solid was removed by filtration and the filtrate was used directly in the next step.

[0401] General procedure for the preparation of compound 6

[0402]

[0403] At 20 °C, NaH2PO4 (7.32 g, 61.05 mmol, 2.0 equiv) in H2O (23 mL) and H2O2 (3.46 g, 30.53 mmol, 30% purity, 1.0 equiv) was added to a solution of compound 5 (11.24 mg, 20.53 mmol, 1.0 equiv) in MeCN (above step). Then NaClO2 (3.31 g, 36.63 mmol, 80% purity, 1.2 equiv) in H2O (30 mL) was added at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The mixture was quenched at 0 °C by adding saturated aqueous Na2S2O3 solution (500 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 6 (11.3 g, crude) as a yellow solid. LCMS of the reaction mixture: Rt = 0.614, MS: 384.0 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.58 (s, 1H), 7.63 (s, 1H), 5.68 (d, J = 7.2 Hz, 1H), 5.09 (s, 1H), 4.83 (d, J = 6.8 Hz, 1H), 2.24 - 2.22 (m, 1H), 1.56 - 1.54 (m, 1H), 1.46 (s, 3H), 1.35 - 1.32 (m, 1H), 1.19 (s, 3H).

[0404] General procedure for the preparation of compound 7

[0405]

[0406] Under N2, to a solution of compound 6 (400 mg, 1.04 mmol, 1.0 equiv) in DCM (10 mL) was added EDCI (399.16 mg, 2.08 mmol, 2.0 equiv), HOBt.NH3 (316.81 mg, 2.08 mmol, 2.0 equiv) and DIPEA (725.3 μl, 4.16 mmol, 4.0 equiv). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between DCM (10 mL × 3) and H2O (15 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate = 1:1 to 0:1) to give 7 (350 mg, 87.7% yield) as a yellow solid. LCMS of the reaction mixture: Rt = 1.990, MS: 383.0 (M+H) + 。 1 HNMR: 400 MHz DMSO-d6 δ (ppm) 8.53 (s, 1H), 7.66 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 5.66 (d, J = 7.2 Hz, 1H), 5.07 (s, 1H), 4.83 - 4.81 (m, 1H), 3.78 - 3.86 (m, 1H), 1.58 - 1.52 (m, 1H), 1.47 (s, 3H), 1.27 - 1.26 (m, 1H), 1.19 (s, 3H).

[0407] General procedure for the preparation of compound 9

[0408]

[0409] To a solution of compound 7 (0.55 g, 1.44 mmol, 1.0 equiv) in NMP (22 mL) was added compound 8 (232.68 mg, 2.87 mmol, 5.5 mL, 2 equiv). The mixture was stirred at 140 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was quenched by adding water (20 mL) at 20 °C and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 9 (0.434 g, 70.6% yield) as a yellow solid. LCMS of the reaction mixture: Rt = 0.591, MS: 428.1 (M+H) + 。

[0410] General procedure for the preparation of compound 11

[0411]

[0412] At 0 °C, Burgess reagent (250.65 mg, 1.05 mmol, 2.0 equiv) was added to a solution of compound 9 (225 mg, 525.91 μmol, 1.0 equiv) in DCM (5 mL). The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between DCM (10 mL * 3) and water (15 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (SiO2, 30% to 70% ethyl acetate / petroleum ether) to give compound 11 as a yellow solid (120 mg, 55.6% yield). LCMS of the reaction mixture: Rt = 0.758, MS: 410.0 (M+H)+. 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.24 (s, 1H), 7.49 (t, J = 6.4 Hz, 1H), 6.60 (s, 1H), 6.30 - 6.04 (m, 1H), 5.53 (d, J = 6.8 Hz, 1H), 5.08 (s, 1H), 4.83 (dd, J = 1.2, 6.8 Hz, 1H), 4.11 - 3.86 (m, 2H), 2.60 - 2.53 (m, 2H), 1.73 - 1.57 (m, 1H), 1.50 (s, 3H), 1.20 (s, 3H).

[0413] General procedure for the preparation of compound 12

[0414]

[0415] HCl / EtOH (0.2 mL, 13.5 M) was added to a solution of compound 11 (100 mg, 244.01 μmol, 1.0 equiv) in toluene (2 mL). The mixture was stirred at 25 °C for 40 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give compound 12 as a white solid (100 mg, crude). The mixture was used directly in the next step. LCMS of the reaction mixture: Rt = 0.571, MS: 416.1 (M+H)+.

[0416] General procedure for the preparation of 14B

[0417]

[0418] To a solution of Compound 12 (50 mg, 110.55 μmol, 1.0 equiv., HCl) in MeOH (1 mL) was added TEA (12.31 mg, 121.6 μmol, 16.93 μl, 1.1 equiv.), followed by addition of formylhydrazine (6.64 mg, 110.55 μmol, 1.0 equiv.). The mixture was stirred at 70 °C for 3 h. LCMS showed completion of the reaction. The mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 5% - 35%, 8 min) to afford 14B as a yellow solid (11.57 mg, 25.4% yield). LCMS: Rt = 1.836, MS: 411.9 (M + H) + 。 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 13.90 - 13.63 (m, 1H), 8.16 (s, 2H), 7.43 (t, J = 6.4 Hz, 1H), 6.55 (s, 1H), 6.33 - 6.01 (m, 1H), 5.48 (br s, 1H), 5.05 (t, J = 6.8 Hz, 1H), 4.82 (s, 2H), 3.99 (s, 2H), 3.88 (t, J = 4.8 Hz, 1H), 1.96 - 1.69 (m, 2H), 1.52 - 1.49 (m, 1H).

[0419] Example 2: Synthesis of 13B and 11B

[0420] Compound 6 was prepared as described for 14B in Example 1

[0421]

[0422] General procedure for the preparation of Compound 8

[0423]

[0424] Compound 8 was prepared as described for Compound 7 in Example 1.

[0425] General procedure for the preparation of Compound 9

[0426]

[0427] At 0 °C, Burgess reagent (1.1 g, 4.70 mmol, 2.0 equiv) was added to a solution of compound 8 (900.0 mg, 2.35 mmol, 1.0 equiv) in DCM (25 mL). The mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 20:1) to afford compound 9 (910.0 mg, crude) as a white oil. LCMS of the reaction mixture: Rt = 0.792, MS: 365.1 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.71 (s, 1H), 7.68 (s, 1H), 5.50 (d, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.94 - 4.92 (m, 1H), 2.72 - 2.69 (m, 1H), 1.71 - 1.67 (m, 1H), 1.49 (s, 3H), 1.45 - 1.41 (m, 1H), 1.19 (s, 3H).

[0428] General procedure for the preparation of compound 10

[0429]

[0430] At 20 °C, EtNH2 (5.48 mmol, 0.36 mL, 4.0 equiv) was added to a solution of compound 9 (500.0 mg, 1.37 mmol, 1.0 equiv) in NMP (5 mL). The resulting mixture was stirred at 140 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was diluted with brine (15 mL) at 20 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 8), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 10 (392.0 mg, crude) as a yellow oil. LCMS of the reaction mixture: Rt = 0.798, MS: 374.2 (M+H) + 。

[0431] General procedure for the preparation of compound 11

[0432]

[0433] To a solution of Compound 10 (250.0 mg, crude) in DMF (5.5 mL) was added NaN3 (130.4 mg, 2.01 mmol, 3.0 equiv) and NH4Cl (107.3 mg, 2.01 mmol, 3.0 equiv). The mixture was stirred at 140 °C for 12 h. LCMS showed completion of the reaction. The reaction mixture was added to water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10:1) to afford Compound 11 (360.0 mg, crude) as a yellow oil. LCMS of the reaction mixture: Rt = 0.701, MS: 417.2 (M+H) + 。

[0434] General procedure for the preparation of Compounds 12 and 12A

[0435]

[0436] At 0 °C, to a solution of Compound 11 (360.0 mg, 863.59 μmol, 1 equiv) in THF (8 mL) and MeOH (2 mL) was added TMSCHN2 (2 M, 526.7 μL, 1.22 equiv). The mixture was stirred at 0 °C for 0.5 h. LCMS showed completion of the reaction. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 20:1) to afford Compound 12 (90.0 mg, 208.87 μmol, 25.00% yield) as a yellow oil and Compound 12A (20.0 mg, 46.42 μmol, 5.56% yield) as a yellow oil. LCMS of the reaction mixture: MS: 431.3 (M+H) + 。Compound 12's 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.07 (s, 1H), 7.15 (t, J = 6.0 Hz, 1H), 6.27 (s, 1H), 5.83 (d, J = 7.2 Hz, 1H), 5.08 (s, 1H), 4.80 - 4.76 (m, 1H), 4.31 (s, 3H), 3.37 (s, 2H), 2.32 - 2.22 (m, 1H), 1.57 (d, J = 7.2 Hz, 2H), 1.50 (s, 3H), 1.24 - 1.16 (m, 6H). Compound 12A's 11H NMR: 400 MHz DMSO-d6 δ (ppm) 8.28 (s, 1H), 7.25 - 7.23 (m, 1H), 6.33 (s, 1H), 5.50 (d, J = 6.8 Hz, 1H), 5.14 (s, 1H), 4.81 - 4.79 (m, 1H), 4.15 (s, 3H), 3.41 (s, 2H), 2.63 - 2.55 (m, 1H), 1.67 - 1.65 (m, 1H), 1.56 (s, 3H), 1.51 - 1.50 (m, 1H), 1.23 (s, 3H), 1.19 - 1.17 (m, 3H).

[0437] General procedure for the preparation of 13B

[0438]

[0439] At 40 °C, a mixture of compound 12 (85.0 mg, 197.27 μmol, 1 equiv) in TFA (10 mL, 30% purity) was stirred for 2 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 10% - 40%, 8 min) to obtain 13B as a white solid (26.0 mg, 66.53 μmol, 33.7% yield). LCMS of the reaction mixture: Rt = 0.635, MS: 391.2 (M + H) + . 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 7.98 (s, 1H), 7.15 (t, J = 6.0 Hz, 1H), 6.33 (s, 1H), 5.50 (d, J = 4.4 Hz, 1H), 5.12 (t, J = 6.8 Hz, 1H), 4.92 (d, J = 8.0 Hz, 1H), 4.83 (s, 1H), 4.34 (s, 3H), 3.95 (t, J = 5.2 Hz, 1H), 3.40 (s, 2H), 1.99 - 1.93 (m, 2H), 1.52 - 1.51 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H). LCMS: Rt = 2.193, MS: 391.1 (M + H) + .

[0440] General procedure for the preparation of 11B

[0441]

[0442] At 40 °C, a mixture of compound 12A (20.0 mg, 46.42 μmol, 1.0 equiv) in TFA (5 mL, 30% purity) was stirred for 2 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to obtain 11B as a white solid (4.0 mg, 10.23 μmol, 22.0% yield). LCMS of the reaction mixture: Rt = 0.635, MS: 391.3 (M+H) + 。 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 8.52 (s, 1H), 7.22 (t, J = 6.0 Hz, 1H), 6.36 (s, 1H), 5.76 - 5.73 (m, 1H), 5.23 (d, J = 8.8 Hz, 1H), 4.90 (s, 1H), 4.62 (t, J = 6.8 Hz, 1H), 4.19 (s, 3H), 3.90 (t, J = 5.6 Hz, 1H), 3.43 (s, 2H), 2.20 - 2.18 (m, 1H), 2.06 (t, J = 4.8 Hz, 1H), 1.35 - 1.33 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H). LCMS: Rt = 2.363, MS: 391.2 (M+H) + 。

[0443] Example 3: Synthesis of 8B

[0444] Compound 8 was prepared as in Example 2 for 13B

[0445]

[0446] General procedure for the preparation of compound 10

[0447]

[0448] At 20 °C, to a solution of compound 8 (0.66 g, 1.81 mmol, 1 equiv) in NMP (10 mL) was added compound 9 (413.58 mg, 2.35 mmol, 1.3 equiv). The resulting mixture was stirred at 140 °C for 24 h. At 20 °C, another portion of compound 9 (159.07 mg, 903.58 μmol, 0.5 equiv) and DIEA (233.56 mg, 1.81 mmol, 314.78 μL, 1 equiv) were added dropwise to the cooled mixture. The resulting mixture was stirred at 140 °C for 36 h. At 20 °C, another portion of compound 9 (159.07 mg, 903.58 μmol, 0.5 equiv) was added dropwise to the mixture. The resulting mixture was stirred at 140 °C for 72 h. Several new peaks were shown on LC-MS, and about 16% of the desired compound was detected. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1, 4 / 1, 1 / 1 to 0 / 1). Compound 10 (1.1 g, crude) as a yellow solid was obtained. LCMS: Rt = 0.911, MS: 506.2 (M+H) + HPLC: Rt = 3.131.

[0449] General procedure for the preparation of compound 11

[0450]

[0451] A mixture of compound 10 (500 mg, 990.50 μmol, 1 equiv) and HCl / MeOH (4 M, 40.00 mL, 161.53 equiv) was degassed and purged with N2 three times, then the mixture was stirred at 20 °C under a N2 atmosphere for 48 h. Several new peaks were shown on LC-MS, and about 44.1% of the desired compound was detected. The mixture was concentrated under reduced pressure to afford compound 11 (550 mg, crude) as a yellow solid. LCMS: Rt = 0.674, MS: 498.3 (M+H) + .

[0452] General procedure for the preparation of compound 13

[0453]

[0454] At 20 °C, 2,2 - diethoxyethylamine (201.08 mg, 1.51 mmol, 219.52 μL, 1.5 equiv) was added dropwise to a solution of compound 11 (500 mg, 1.01 mmol, 1 equiv) in MeOH (10 mL). After the addition, the mixture was stirred at 20 °C for 12 h. Several new peaks were shown on LC - MS, and about 68.2% of the desired compound was detected. The mixture was directly used for the next step. LCMS: Rt = 0.750, MS: 599.4 (M + H) + 。

[0455] General procedure for the preparation of 9B

[0456]

[0457] A mixture of compound 13 (600 mg, 682.37 μmol, 68% purity, 1 equiv) in HCl (5 M, 24.48 mL, 179.38 equiv) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C under a N2 atmosphere for 1 h. Several new peaks were shown on LC - MS, and about 70.6% of the desired compound was detected. The reaction mixture was basified with saturated aqueous NaHCO3 to adjust the pH > 7, and then diluted with 20 mL of water and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). 9B was obtained as a white solid (280 mg, 81.13% yield). LCMS: Rt = 0.691, MS: 505.3 (M + H) + 。 1 1H NMR: DMSO - d6 δ (ppm) = 11.95 (br s, 1H), 8.35 (s, 1H), 7.80 (br t, J = 5.7 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.97 (s, 2H), 6.35 (br s, 1H), 5.42 (d, J = 4.5 Hz, 1H), 4.98 (br t, J = 6.5 Hz, 1H), 4.87 - 4.69 (m, 4H), 3.84 (br t, J = 5.3 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.44 (td, J = 1.9, 3.6 Hz, 1H).

[0458] General procedure for the preparation of 8B

[0459]

[0460] At 20 °C, ZnCN2 (44.26 mg, 376.92 μmol, 23.92 μL, 1.27 equiv) and Pd(dppf)Cl2 (21.70 mg, 29.66 μmol, 0.1 equiv) were added dropwise to a solution of 9B (150 mg, 296.57 μmol, 1 equiv) in DMF (8 mL) under N2. After the addition, the mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by adding 10 mL of water at 20 °C, and extracted with EA (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by a preparative HPLC column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 25% - 50%, 8 min. 8B (20 mg, 39.73 μmol, 13.40% yield, 98.6% purity) was obtained as a yellow solid. LCMS: Rt = 0.726, MS: 496.2 (M+H) + 。HPLC: Rt = 2.158. LCMS: Rt = 2.670, MS: 495.9 (M+H) + 。 1 1H NMR: DMSO-d6 δ (ppm) = 11.85 (br s, 1H), 8.63 - 8.52 (m, 1H), 8.01 - 7.90 (m, 1H), 7.58 - 7.49 (m, 1H), 7.41 - 7.30 (m, 2H), 7.08 - 6.82 (m, 3H), 5.45 (d, J = 4.5 Hz, 1H), 4.79 - 4.75 (m, 1H), 3.91 - 3.80 (m, 1H), 1.88 - 1.73 (m, 2H), 1.50 - 1.38 (m, 1H).

[0461] Example 4: Synthesis of 9B

[0462] Compound 10 was prepared as described for 8B in Example 3

[0463]

[0464] General procedure for the preparation of compound 11

[0465]

[0466] A mixture of Compound 10 (500 mg, 990.50 μmol, 1 equiv), HCl / MeOH (4 M, 40.00 mL, 161.53 equiv) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C under a N2 atmosphere for 48 h. Several new peaks were shown on LC-MS, and about 44.1% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give Compound 11 (550 mg, crude) as a yellow solid. LCMS: Rt = 0.674, MS: 498.3 (M+H) + 。

[0467] General procedure for the preparation of Compound 13

[0468]

[0469] At 20 °C, 2,2 - diethoxyethylamine (201.08 mg, 1.51 mmol, 219.52 μL, 1.5 equiv) was added dropwise to a solution of Compound 11 (500 mg, 1.01 mmol, 1 equiv) in MeOH (10 mL). After the addition, the mixture was stirred at 20 °C for 12 h. Several new peaks were shown on LC-MS, and about 68.2% of the desired compound was detected. The mixture was directly used for the next step. LCMS: Rt = 0.750, MS: 599.4 (M+H) + 。

[0470] General procedure for the preparation of 9B

[0471]

[0472] A mixture of Compound 13 (600 mg, 682.37 μmol, 68% purity, 1 equiv) in HCl (5 M, 24.48 mL, 179.38 equiv) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C under a N2 atmosphere for 1 h. Several new peaks were shown on LC-MS, and about 70.6% of the desired compound was detected. The reaction mixture was basified with saturated aqueous NaHCO3, adjusted to pH > 7, and then diluted with 20 mL of water and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). 9B (280 mg, 553.60 μmol, 81.13% yield) was obtained as a white solid. LCMS: Rt = 0.691, MS: 505.3 (M+H) + 。 11H NMR: DMSO-d6 δ (ppm) = 11.95 (br s, 1H), 8.35 (s, 1H), 7.80 (br t, J = 5.7 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.97 (s, 2H), 6.35 (br s, 1H), 5.42 (d, J = 4.5 Hz, 1H), 4.98 (br t, J = 6.5 Hz, 1H), 4.87 - 4.69 (m, 4H), 3.84 (br t, J = 5.3 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.44 (td, J = 1.9, 3.6 Hz, 1H).

[0473] Example 5: Synthesis of 12B

[0474] Compound 10 was prepared as in Example 2 for 13B and 11B.

[0475]

[0476] General procedure for the preparation of Compound 13

[0477]

[0478] At 20 °C, a mixture of Compound 10 (200.0 mg, 534.99 μmol, 1.0 equiv) in MeOH / HCl (10 mL, 4 M) was stirred for 4 h. Then the solution was cooled to 0 °C, AcOH (1.07 mmol, 61.2 μL, 2.0 equiv) and Compound 12 (534.99 μmol, 77.7 μL, 1.0 equiv) were added, and the mixture was stirred at 70 °C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was used directly for the next step. LCMS of the reaction mixture: Rt = 0.644, MS: 467.3 (M + H) + .

[0479] General procedure for the preparation of 12B

[0480]

[0481] At 80 °C, the reaction mixture from the above step in an HCl aqueous solution (5.0 M, 10 mL) was stirred for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters XbridgePrep OBD C18 150*40 mm*10 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 5%-35%, 8 min) to obtain 12B as a white solid (22.0 mg, 58.69 μmol). LCMS of the reaction mixture: Rt = 0.565, MS: 375.2 (M+H) + . 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 11.82 (s, 1H), 8.30 (s, 1H), 7.15 (t, J = 6.0 Hz, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 6.35 (s, 1H), 5.41 (d, J = 2.0 Hz, 1H), 4.97 (t, J = 6.4 Hz, 1H), 4.83 (s, 1H), 4.77 (d, J = 7.6 Hz, 1H), 3.81 (d, J = 6.0 Hz, 1H), 3.42 (s, 2H), 1.80 - 1.77 (m, 1H), 1.76 - 1.73 (m, 1H), 1.44 - 1.43 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H). LCMS: Rt = 2.099, MS: 375.1 (M+H) + .

[0482] Example 6: Synthesis of 10B

[0483] Compound 6 was prepared as in Example 1 for 14B

[0484]

[0485] General procedure for the preparation of compound 8

[0486]

[0487] At 0 °C, HOBt (116.05 mg, 858.90 μmol, 1.1 eq) and EDCI (164.65 mg, 858.90 μmol, 1.1 eq) were added dropwise to a solution of compound 6 (300 mg, 780.82 μmol, 1 eq) and 7 (104.00 mg, 780.82 μmol, 113.53 μL, 1.0 eq) in DCM (37 mL). After stirring the resulting mixture at 20 °C for 12 h, several new peaks were shown on LC-MS and about 36.5% of the desired compound was detected. The reaction mixture was quenched by adding H2O (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1) and compound 8 (0.31 g, 620.76 μmol, 79.50% yield) was obtained as a white solid. LCMS of the reaction mixture: Rt = 0.812, MS: 499.3 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6. δ (ppm) 8.53 (s, 1H), 7.73 - 7.56 (m, 2H), 5.67 (br d, J = 7.0 Hz, 1H), 5.08 (s, 1H), 4.83 (br d, J = 7.3 Hz, 1H), 4.53 (brt, J = 5.3 Hz, 1H), 3.65 - 3.52 (m, 3H), 3.49 - 3.35 (m, 3H), 3.29 - 3.21 (m, 1H), 3.13 - 3.03 (m, 1H), 2.18 (br dd, J = 5.6, 9.1 Hz, 1H), 1.56 - 1.44 (m, 4H), 1.29 (br t, J = 5.0 Hz, 2H), 1.25 - 1.16 (m, 5H), 1.13 - 1.06 (m, 4H).

[0488] General procedure for the preparation of compound 9

[0489]

[0490] At 20 °C, HCl (3 M, 1.86 mL, 8.99 equiv) was added dropwise to a solution of compound 8 (310 mg, 620.76 μmol, 1 equiv) in acetone (50 mL). The resulting mixture was stirred at 20 °C for 2 h. Several new peaks were shown on LC-MS, and about 73.87% of the desired compound was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1). Compound 9 (0.320 g, crude) was obtained as a white solid. LCMS of the reaction mixture: Rt = 0.636, MS: 443.2 (M+H) + 。 1 H NMR: 400 MHz DMSO-d 6. δ (ppm) 9.45 (s, 1H), 8.58 (s, 1H), 8.33 (br t, J = 4.8 Hz, 1H), 7.65 (s, 1H), 5.76 (s, 1H), 5.69 (br d, J = 7.6 Hz, 1H), 5.16 - 5.04 (m, 2H), 4.92 - 4.77 (m, 2H), 2.21 - 2.20 (m, 1H), 1.58 - 1.51 (m, 3H), 1.50 - 1.48 (m, 4H), 1.21 (s, 5H)

[0491] General procedure for the preparation of compound 10

[0492]

[0493] At 0 °C, Burgess reagent (358.64 mg, 1.50 mmol, 2 equiv) was added to a solution of compound 9 (320 mg, 752.47 μmol, 1 equiv) in DCM (5 mL). After the addition, the mixture was stirred at 20 °C for 1 h, then at 40 °C for 2 h. Several new peaks were shown on LC-MS, and about 17.39% of the desired compound was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1). Compound 10 (0.14 g, 45.69% yield) was obtained as a white solid. LCMS of the reaction mixture: Rt = 0.802, MS: 407.1 (M+H) + 。

[0494] General procedure for the preparation of Compound 11

[0495]

[0496] At 20 °C, EtNH2 (31.00 mg, 687.54 μmol, 44.99 μL, 2 eq) was added dropwise to a solution of Compound 10 (0.14 g, 343.77 μmol, 1 eq) in NMP (5 mL). After the addition, the resulting mixture was stirred at 140 °C for 12 h. Several new peaks were shown on LC-MS, and about 6% of the desired compound was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1). Compound 11 (150 mg, crude) was obtained as a white solid. LCMS of the reaction mixture: Rt = 0.786, MS: 416.2 (M+H) + 。

[0497] General procedure for the preparation of 10B

[0498]

[0499] At 20 °C, a mixture of Compound 11 (100 mg, 240.46 μmol, 1 eq) in TFA (100 mL, 30% purity) was stirred for 12 h. Several new peaks were shown on LC-MS, and about 61.4% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 10% - 40%, 8 min to give Compound 10B (22 mg, 58.54 μmol, 24.35% yield) as a white solid. LCMS of the reaction mixture: Rt = 0.626, MS: 376.2 (M+H) + 。 11H NMR: 400 MHz MeOD. δ (ppm) 8.03 (d, J = 0.8 Hz, 1H), 7.98 (s, 1H), 7.19 - 7.11 (m, 2H), 6.33 (s, 1H), 5.50 (d, J = 4.8 Hz, 1H), 5.15 - 5.07 (m, 1H), 4.97 (d, J = 8.0 Hz, 1H), 4.78 (d, J = 1.1 Hz, 1H), 3.97 (dt, J = 1.6, 4.8 Hz, 1H), 3.40 (br s, 2H), 2.03 (dd, J = 4.8, 8.8 Hz, 1H), 1.89 (t, J = 4.8 Hz, 1H), 1.52 (ddd, J = 1.2, 4.8, 8.8 Hz, 1H), 1.23 (br s, 1H), 1.16 (t, J = 7.2 Hz, 3H).

[0500] Example 7: Synthesis of 3B

[0501]

[0502]

[0503] General procedure for the preparation of compound 2

[0504]

[0505] At 20 °C, DHP (26.8 g, 319.13 mmol, 3.0 equiv) and TsOH·Py (2.7 g, 10.64 mmol, 0.1 equiv) were added to a solution of compound 1 (20.0 g, 106.38 mmol, 1.0 equiv) in THF (400 mL). The resulting mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 2:1) to afford compound 2 (27.0 g, 99.22 mmol, 93.3% yield) as a white solid. LCMS of the reaction mixture: Rt = 0.802, MS: 272.0 (M + H) + . 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.81 (s, 1H), 7.66 (s, 1H), 5.74 - 5.71 (m, 1H), 4.07 - 3.96 (m, 1H), 3.79 - 3.65 (m, 1H), 2.32 - 2.12 (m, 1H), 2.03 - 1.93 (m, 2H), 1.83 - 1.70 (m, 1H), 1.64 - 1.56 (m, 2H).

[0506] General procedure for the preparation of compound 3

[0507]

[0508] At -70 °C, under N2, LiHMDS (1.0 M, 271.0 mL, 2.5 equiv) was added dropwise to a solution of compound 2 (29.5 g, 108.40 mmol, 1.0 equiv), TIPSCl (162.61 mmol, 34.8 mL, 1.5 equiv), and HMPA (1.08 mol, 190.5 mL, 10 equiv) in THF (400 mL). The mixture was stirred at -70 °C for 5 h. TLC (petroleum ether / ethyl acetate = 3:1) showed the reaction was complete. The reaction was quenched by adding saturated NH4Cl solution (600 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO2, 0% to 2% ethyl acetate / petroleum ether) to afford compound 3 (33.0 g, 77.02 mmol, 71.1% yield) as a white solid. LCMS of the reaction mixture: Rt = 1.210, MS: 344.1 (M-THP+H) + 。 1 1H NMR: 400 MHz chloroform δ (ppm) 7.24 (s, 1H), 5.45 (dd, J = 2.2, 11.1 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.63 (dt, J = 2.1, 12.0 Hz, 1H), 3.41 - 3.26 (m, 1H), 2.20 - 2.09 (m, 1H), 1.98 - 1.76 (m, 2H), 1.71 - 1.54 (m, 5H), 1.20 (dd, J = 1.4, 7.6 Hz, 18H).

[0509] General procedure for the preparation of compound 4

[0510]

[0511] At -78 °C, LDA (2.0 M, 17.2 mL, 7.4 equiv) was added dropwise to a solution of compound 3 (2.0 g, 4.67 mmol, 1.0 equiv) in THF (35 mL) under N₂. The mixture was stirred at -78 °C for 30 min, and then I₂ (1.2 g, 4.67 mmol, 1 equiv) in THF (15 mL) was added dropwise to the mixture at -78 °C under N₂. The mixture was stirred at -78 °C for 10 min. TLC (petroleum ether:ethyl acetate) showed a major new more polar spot. The mixture was quenched at 0 °C by adding saturated aqueous NH₄Cl solution (20 mL) and saturated aqueous Na₂SO₃ solution (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 4 (2.5 g, 4.51 mmol, 96.6% yield) as a white solid. 1 ¹H NMR: 400 MHz chloroform δ (ppm) 5.44 - 5.41 (m, 1H), 4.21 - 4.17 (m, 1H), 3.65 - 3.59 (m, 1H), 3.29 - 3.25 (m, 1H), 2.15 - 2.13 (m, 1H), 1.99 - 1.76 (m, 2H), 1.73 - 1.50 (m, 5H), 1.27 - 1.18 (m, 18H).

[0512] General procedure for the preparation of compound 5

[0513]

[0514] HCl (12 M, 5.8 mL, 15.5 equiv) was added to a mixture of compound 4 (2.5 g, 4.51 mmol, 1 equiv) in EtOH (25 mL), and then the mixture was stirred at 20 °C for 12 h. Several new peaks were shown on LC-MS, and about 29% of the desired compound was detected. The reaction mixture was filtered and the filter cake was added to saturated aqueous NaHCO₃ solution (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give compound 5 (1.8 g, crude) as a white solid. LCMS of the reaction mixture: Rt = 0.675, MS: 313.9 (M+H) + 。 1 ¹H NMR: DMSO-d₆ δ (ppm) 8.26 (s, 1H).

[0515] General Procedure for the Preparation of Compound 6

[0516]

[0517] To a solution of Compound 5 (1.6 g, crude) in THF (16 mL) was added PPh3 (2.7 g, 10.19 mmol, 2 equiv), followed by the addition of Compound Int.10 (3.4 g, 7.65 mmol, 1.5 equiv) and DIAD (10.19 mmol, 2.0 mL, 2 equiv). The mixture was stirred at 20 °C for 12 h. LC-MS showed that approximately 16% of Compound 5 remained and approximately 10% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 6 / 1 to 0 / 1) to give Compound 6 (5.9 g, crude) as a white oil. LCMS of the reaction mixture: Rt = 1.122, MS: 738.2 (M+H) + 。

[0518] General Procedure for the Preparation of Compound 7

[0519]

[0520] At 30 °C, AcOH (375.32 mmol, 26.8 mL, 80.0% purity, 94.0 equiv) was added dropwise to a solution of Compound 6 (4.4 g, crude) in MeCN (17.7 mL). The reaction mixture was stirred at 30 °C for 11 h. Then AcOH (174.85 mmol, 12.5 mL, 80.0% purity, 43.8 equiv) and MeCN (6 mL) were added at 30 °C. The resulting mixture was stirred at 30 °C for 1 h. LC-MS showed that approximately 24% of Compound 6 remained and approximately 33% of Compound 7 was detected. The reaction mixture was basified to pH ~8 with NH3.H2O and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 1:3) to afford Compound 7 (600.0 mg, 1.21 mmol, 30.3% yield) as a white solid. LCMS of the reaction mixture: Rt = 0.804, MS: 496.1 (M+H) + 。 11H NMR: 400 MHz in CDCl3 δ (ppm) 8.24 (s, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.92 (s, 1H), 4.68 (d, J = 7.2 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 3.54 (d, J = 12 Hz, 1H), 2.51 (s, 1H), 1.72 - 1.69 (m, 1H), 1.56 (s, 3H), 1.25 (s, 3H), 1.21 - 1.18 (m, 1H), 1.03 - 1.01 (m, 1H).

[0521] General procedure for the preparation of compound 8

[0522]

[0523] At 20 °C, IBX (521.0 mg, 1.86 mmol, 1.3 equiv) was added to a solution of compound 7 (710.0 mg, 1.43 mmol, 1 equiv) in MeCN (10 mL). The mixture was stirred at 80 °C for 1 h. Then, IBX (200.3 mg, 715.54 μmol, 0.5 equiv) was added at 20 °C. The mixture was stirred at 80 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:1) showed completion of the reaction. The solid was removed by filtration and the filtrate was used directly for the next step.

[0524] General procedure for the preparation of compound 9

[0525]

[0526] At 20 °C, a solution of NaH2PO4 (343.3 mg, 2.86 mmol, 2 equiv) in H2O (3.5 mL) and H2O2 (1.43 mmol, 0.15 mL, 30.0% purity, 1.0 equiv) was added to a solution of compound 8 (from the above step). Then, a solution of NaClO2 (155.3 mg, 1.72 mmol, 1.2 equiv) in H2O (4.0 mL) was added at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:1) showed completion of the reaction. The reaction mixture was quenched at 0 °C by adding saturated aqueous Na2SO3 solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to afford compound 9 as a white solid (600.0 mg, 1.18 mmol, 82.2% yield).

[0527] General procedure for the preparation of compound 10

[0528]

[0529] Under N2, to a solution of compound 9 (4.70 g, 9.21 mmol, 1 equiv) in THF (100 mL) was added EDCI (3.53 g, 18.43 mmol, 2 equiv), HOBt·NH3 (2.80 g, 18.43 mmol, 2 equiv) and DIEA (36.85 mmol, 6.42 mL, 4 equiv). The mixture was stirred at 30 °C for 12 h. Several new peaks were shown on LC-MS and about 36% of the desired compound was detected. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 10 (4.00 g) as a white solid. LCMS: Rt = 0.729, MS: 509.0 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.51 (s, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 5.65 (d, J = 6.8 Hz, 1H), 5.05 (s, 1H), 4.84 (d, J = 6.8 Hz, 1H), 2.19 - 2.17 (m, 1H), 1.52 - 1.51 (m, 1H), 1.46 (s, 3H), 1.26 - 1.24 (m, 1H), 1.19 (s, 3H).

[0530] General procedure for the preparation of compound 11

[0531]

[0532] At 0 °C, Burgess reagent (3.65 g, 15.32 mmol, 2 equiv) was added to a solution of compound 10 (3.90 g, 7.66 mmol, 1 equiv) in DCM (120 mL). The mixture was stirred at 20 °C for 1 h. Several new peaks were shown on LC-MS, and about 84% of the desired compound was detected. The reaction mixture was diluted with H2O (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 11 (3.00 g) as a white solid. LCMS: Rt = 0.836, MS: 490.9 (M+H )+ 。

[0533] General procedure for the preparation of compound 12

[0534]

[0535] DBTO (0.39 g, 1.57 mmol, 0.3 equiv) and TMSN3 (25.76 mmol, 3.40 mL, 5 equiv) were added to a solution of compound 11 (2.53 g, 5.15 mmol, 1 equiv) in toluene (51 mL). The mixture was stirred at 100 °C for 12 h. Several new peaks were shown on LC-MS, and about 60% of the desired compound was detected. The reaction mixture was dried with N2 to remove the solvent to give compound 12 (2.80 g, crude) as a yellow oil. LCMS: Rt = 0.638, MS: 534.0 (M+H) + 。

[0536] General procedure for the preparation of compound 13

[0537]

[0538] At 0 °C, TMSCHN2 (2 M, 3.40 mL, 1.3 equiv) was added to a solution of compound 12 (2.80 g, 5.24 mmol, 1 equiv) in THF (40 mL) and MeOH (10 mL). The mixture was stirred at 0 °C for 0.5 h. Several new peaks were shown on LC-MS, and about 65% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 13 (2.00 g, crude) as a white solid. LCMS: Rt = 0.850, MS: 548.1 (M+H) + 。1 1H NMR: In CDCl3, δ (ppm) 8.07 (s, 1H), 6.01 (d, J = 7.2 Hz, 1H), 5.08 (s, 1H), 4.82 - 4.80 (m, 1H), 4.34 (s, 3H), 2.39 - 2.37 (m, 1H), 1.77 - 1.74 (m, 2H), 1.61 (s, 3H), 1.32 (s, 3H).

[0539] General procedure for the preparation of Compound 14

[0540]

[0541] At 20 °C, NH3·H2O (28.85 mmol, 4.44 mL, 25% purity, 15.8 equiv) was added to a solution of Compound 13 (1.00 g, 1.82 mmol, 1 equiv) in NMP (10 mL). The resulting mixture was stirred at 140 °C for 24 h. Several new peaks were shown on LC-MS, and approximately 21% of the desired compound was detected. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound 14 (1.80 g, crude) as a white solid. LCMS: Rt = 0.680, MS: 529.1 (M + H) + 。

[0542] General procedure for the preparation of Compound 16

[0543]

[0544] Under N2, Brettphos Pd G1 (45.32 mg, 56.74 μmol, 0.1 equiv) was added to a solution of Compound 14 (300 mg, 567.39 μmol, 1.0 equiv) and Compound 15 (101.2 mg, 737.61 μmol, 1.3 equiv) in THF (6 mL). Then LiHMDS (1 M, 1.42 mL, 2.5 equiv) was added dropwise. The resulting mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc (20 mL × 3) and H2O (30 mL). The organic phase was separated, washed with brine (25 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by preparative TLC (DCM / MeOH = 20 / 1) to give Compound 16 (200 mg, 371.75 μmol, 65.5% yield) as a yellow solid. LCMS: Rt = 0.681, MS: 538.3 (M + H)+ 。 1 1H NMR: DMSO-d6 δ (ppm) 8.09 - 8.04 (m, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.37 (s, 2H), 5.83 (d, J = 7.2 Hz, 1H), 5.05 (s, 1H), 4.78 (d, J = 6.0 Hz, 1H), 4.31 (s, 3H), 3.88 - 3.80 (m, 2H), 3.77 - 3.69 (m, 4H), 2.28 (t, J = 6.8 Hz, 1H), 1.57 (d, J = 6.4 Hz, 2H), 1.50 (s, 3H), 1.24 (s, 3H).

[0545] General procedure for the preparation of Compound 18

[0546]

[0547] At 20 °C, Compound 17 (241.2 mg, 1.49 mmol, 4 eq) and AcOH (446.5 mg, 7.43 mmol, 20 eq) were added to a solution of Compound 16 (200 mg, 371.75 μmol, 1.0 eq) in ACN (3 mL). The mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc (15 mL × 3) and H2O (20 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give Compound 18 (100 mg, crude) as a yellow solid. LCMS: Rt = 0.772, MS: 562.4 (M + H) + 。

[0548] General procedure for the preparation of 3B

[0549]

[0550] Compound 18 (100 mg, 177.93 μmol, 1.0 eq) was dissolved in TFA (10 mL) and the mixture was stirred at 90 °C for 4 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure and then purified by preparative HPLC (column: Phenomenex C18 75 × 30 mm × 3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 1% - 30%, 8 min) to give 3B (32 mg, 79.21 μmol, 44.5% yield, 99.5% purity) as a white solid. LCMS: Rt = 1.782, MS: 402.1 (M + H) + 。 11H NMR: 400 MHz DMSO-d6 δ (ppm) 13.33 (s, 1H), 8.26 (s, 1H), 5.54 (d, J = 4.4 Hz, 1H), 5.17 (t, J = 7.2 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.97 (d, J = 8.0 Hz, 1H), 4.35 (s, 3H), 4.01 (t, J = 5.4 Hz, 1H), 2.60 - 2.54 (m, 3H), 2.06 (dd, J = 4.4, 8.4 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.60 - 1.49 (m, 1H).

[0551] Example 8: Synthesis of 2B and 7B

[0552] Compound 10 was prepared as described for 3B in Example 7

[0553]

[0554] General procedure for the preparation of compound 11

[0555]

[0556] To a solution of compound 10 (600 mg, 883.87 μmol, 75% purity, 1.0 equiv) in NMP (10 mL) was added NH3·H2O (7.50 g, 53.49 mmol, 8.24 mL, 25% purity, 60.51 equiv). The mixture was stirred at 140 °C for 16 h. LCMS showed completion of the reaction. The reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (50 mL). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to afford compound 11 as a yellow solid (400 mg, 816.84 μmol, 92.4% yield). LCMS: Rt = 0.665, MS: 490.1 (M+H) + 。

[0557] General procedure for the preparation of compound 13

[0558]

[0559] At 25 °C, under N2, Et3N (1.49 g, 14.70 mmol, 2.05 mL, 15 equiv), KF (683.40 mg, 11.76 mmol, 275.56 μL, 12 equiv), CuI (37.34 mg, 196.04 μmol, 0.2 equiv), and Pd(PPh3)2Cl2 (137.60 mg, 196.04 μmol, 0.2 equiv) were added to a mixture of compound 11 (480 mg, 980.20 μmol, 1.0 equiv) and compound 12 (1.10 g, 9.80 mmol, 1.45 mL, 10 equiv) in DMF (10 mL). The mixture was stirred at 60 °C for 1 h. LCMS showed the reaction was complete. The solid was removed by filtration, and the filtrate was partitioned between ethyl acetate (10 mL × 3) and H2O (20 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (SiO2, 50% - 100% ethyl acetate / petroleum ether) to afford compound 13 (310 mg) as a yellow solid. LCMS: Rt = 0.675, MS: 402.3 (M + H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.16 - 7.98 (m, 1H), 7.23 - 6.77 (m, 4H), 5.63 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.72 (d, J = 6.4 Hz, 1H), 2.19 - 2.12 (m, 3H), 2.12 - 2.07 (m, 1H), 1.51 (dd, J = 4.8, 8.8 Hz, 1H), 1.46 (s, 3H), 1.25 (t, J = 5.2 Hz, 1H), 1.19 (d, J = 1.6 Hz, 3H).

[0560] General procedure for the preparation of compound 14

[0561]

[0562] To a solution of compound 13 (300 mg, 746.55 μmol, 1.0 equiv) in DMF (5 mL) was added t-BuOK (209.43 mg, 1.87 mmol, 2.5 equiv). The mixture was stirred at 60 °C for 16 h. TLC (DCM / MeOH = 10 / 1) showed completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 mL × 3) and H2O (20 mL). The combined organic layers were washed with brine (15 mL × 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (SiO2, 50% to 100% ethyl acetate / petroleum ether) to give compound 14 as a yellow solid (250 mg, 622.13 μmol, 83.3% yield). LCMS of the reaction mixture: Rt = 0.655, MS: 402.3 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 12.36 (s, 1H), 8.21 (s, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 6.33 (s, 1H), 5.76 - 5.68 (m, 1H), 5.11 (s, 1H), 4.82 - 4.69 (m, 1H), 2.47 - 2.39 (m, 3H), 2.15 (dd, J = 5.8, 8.8 Hz, 1H), 1.55 (dd, J = 4.8, 8.8 Hz, 1H), 1.51 - 1.46 (m, 3H), 1.30 (t, J = 5.1 Hz, 1H), 1.20 (s, 3H).

[0563] General procedure for the preparation of compound 15

[0564]

[0565] To a solution of compound 14 (200 mg, 497.70 μmol, 1.0 equiv) in toluene (5 mL) was added DMF-DMA (177.92 mg, 1.49 mmol, 198.35 μL, 3.0 equiv). The mixture was stirred at 110 °C for 1 h. LCMS showed completion of the reaction. The mixture was concentrated under reduced pressure and then used directly for the next step. LCMS of the reaction mixture: Rt = 0.545, MS: 457.4 (M+H) + 。

[0566] General procedure for the preparation of compound 17

[0567]

[0568] To a solution of Compound 15 (227 mg, 496.80 μmol, 1.0 eq) in AcOH (5 mL) was added Compound 16 (62.94 mg, 546.48 μmol, 40% purity, 1.1 eq). The mixture was stirred at 45 °C for 1 h. LCMS showed the reaction was complete. The solvent was removed and the resulting residue was partitioned between ethyl acetate (15 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water (10 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated to give Compound 17 and Compound 17-1 (200 mg, crude) as a yellow solid. LCMS: Rt = 0.591, 0.639, MS: 440.4 (M+H) + 。

[0569] General procedure for the preparation of 2B, 7B

[0570]

[0571] Compound 17 and Compound 17-1 (220 mg, 500.12 μmol, 1.0 eq) were dissolved in TFA (1 mL, 30% aqueous solution). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 10% - 40%, 8 min) to give 2B (18.5 mg, 8.80% yield, 95.16% purity) as a white solid. LCMS: Rt = 2.198, MS: 400.0 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 12.31 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 6.33 (s, 1H), 5.44 (d, J = 4.4 Hz, 1H), 5.14 - 5.06 (m, 1H), 4.99 (s, 1H), 4.72 (d, J = 8.0 Hz, 1H), 3.90 (dd, J = 4.8, 6.0 Hz, 1H), 3.85 (s, 3H), 2.43 - 2.40 (m, 3H), 1.90 - 1.82 (m, 1H), 1.79 (dd, J = 4.4, 8.4 Hz, 1H), 1.49 (td, J = 3.6, 5.2 Hz, 1H). And 7B (33.9 mg, 16.14% yield, 95.19% purity) as a white solid. LCMS: Rt = 2.288, MS: 400.0 (M+H)+ . 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 12.36 (s, 1H), 8.96 (s, 1H), 7.95 (s, 1H), 6.34 (s, 1H), 5.70 (d, J = 4.8 Hz, 1H), 5.12 (d, J = 9.2 Hz, 1H), 5.08 (s, 1H), 4.57 - 4.49 (m, 1H), 3.99 (s, 3H), 3.87 - 3.78 (m, 1H), 2.45 - 2.42 (m, 3H), 2.13 - 2.06 (m, 2H), 1.31 - 1.23 (m, 1H).

[0572] Example 9: Synthesis of 1B, 5B, 4B

[0573] Compound 14 was prepared as described for 3B in Example 7

[0574]

[0575]

[0576] General procedure for the preparation of compound 14

[0577]

[0578] At 20 °C, NH3·H2O (28.85 mmol, 4.44 mL, 25% purity, 15.8 equiv) was added to a solution of compound 13 (1.00 g, 1.82 mmol, 1 equiv) in NMP (10 mL). The resulting mixture was stirred at 140 °C for 24 h. Several new peaks were shown on LC-MS, and about 21% of the desired compound was detected. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 14 as a white solid (1.80 g, crude). LCMS: Rt = 0.680, MS: 529.1 (M + H) + .

[0579] General procedure for the preparation of compound 16

[0580]

[0581] At 25 °C, under N2, TEA (28.74 mmol, 4.0 mL, 30.39 equiv), CuI (36.0 mg, 189.13 μmol, 0.2 equiv), and Pd(PPh3)2Cl2 (132.7 mg, 189.13 μmol, 0.2 equiv) were added to a mixture of compound 14 (500 mg, 945.66 μmol, 1 equiv) and compound 15 (10.16 mmol, 600.0 μL, 10.74 equiv) in DMF (20 mL). The mixture was stirred at 60 °C for 12 h. LCMS showed the reaction was complete. The solid was removed by filtration, and the filtrate was partitioned between EtOAc (20 mL x 3) and H2O (70 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO2, 50% - 100% EA / PE) to give compound 16 (500 mg, crude) as a brown solid. LCMS: Rt = 0.690, MS: 457.2 (M+H) + 。

[0582] General procedure for the preparation of compound 17

[0583]

[0584] At 20 °C, t-BuOK (313.1 mg, 2.79 mmol, 2.5 equiv) was added to a solution of compound 16 (510 mg, crude) in DMF (52 mL). The resulting mixture was stirred at 40 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 1 / 0 to 10 / 1) to give compound 17 (240 mg, 47.06% yield) as a brown solid. LCMS: Rt = 0.570, MS: 457.2 (M+H) + 。

[0585] General procedure for the preparation of compound 18

[0586]

[0587] At 20 °C, IBX (167.3 mg, 597.52 μmol, 1.3 equiv) was added to a solution of compound 17 (210 mg, 459.63 μmol, 1 equiv) in ACN (21 mL). The resulting mixture was stirred at 80 °C for 1 h. Several new peaks were shown on LC-MS, and about 30% of the desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give compound 18 (160 mg, crude) as a brown solid. LCMS: Rt = 0.649, MS: 455.2 (M+H) + 。

[0588] General procedure for the preparation of compound 19

[0589]

[0590] At 20 °C, DAST (857.39 μmol, 113.28 μL, 3 equiv) was added to a solution of compound 18 (130 mg, crude) in DCM (13 mL). The resulting mixture was stirred at 20 °C for 12 h. Several new peaks were shown on LC-MS, and about 35% of the desired compound was detected. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NaHCO3 (30 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 19 (50.0 mg, crude) as a brown solid. LCMS: Rt = 0.678, MS: 477.3 (M+H) + 。

[0591] General procedure for the preparation of 1B

[0592]

[0593] Compound 19 (50.0 mg, crude) was dissolved in TFA (15 mL, 30% purity) and the mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to give 1B (18 mg, 41.21 μmol, 39.30% yield, 100% purity) as a white solid. LCMS: Rt = 1.312, MS: 437.0 (M+H) + 。 11H NMR: 400 MHz DMSO-d6 δ (ppm) 13.23 (br s, 1H), 8.25 (s, 1H), 7.24 (t, J = 54.0 Hz, 1H), 7.00 (s, 1H), 5.54 (d, J = 4.6 Hz, 1H), 5.24 - 5.14 (m, 1H), 5.04 (s, 1H), 4.97 (d, J = 7.9 Hz, 1H), 4.35 (s, 3H), 4.03 (br t, J = 5.4 Hz, 1H), 2.07 (dd, J = 4.6, 8.6 Hz, 1H), 1.99 (t, J = 4.7 Hz, 1H), 1.55 (br dd, J = 4.9, 8.5 Hz, 1H). LCMS: Rt = 2.266, MS: 437.1 (M+H) + 。

[0594] General procedure for the preparation of 5B

[0595]

[0596] A mixture of compound 17 (20.0 mg, 43.77 μmol, 1 equiv) in TFA (4.05 mmol, 1.0 mL, 30% purity, 92.5 equiv) was stirred at 30 °C for 2 h. Several new peaks were shown on LC-MS, and about 67% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 5% - 35%, 8 min) to give 5B as a white solid (5.0 mg, 11.74 μmol, 26.81% yield, 97.85% purity). LCMS: Rt = 0.457, MS: 417.2 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 12.43 (s, 1H), 8.17 (s, 1H), 6.49 (s, 1H), 5.55 (d, J = 4.8 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 5.16 (t, J = 5.6 Hz, 1H), 5.02 (s, 1H), 4.97 (d, J = 8.4 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.35 (s, 3H), 4.00 - 3.99 (m, 1H), 2.06 - 2.03 (m, 1H), 2.01 - 1.98 (m, 1H), 1.56 - 1.54 (m, 1H). LCMS: Rt = 1.866, MS: 417.1 (M+H) + 。

[0597] General procedure for the preparation of 4B

[0598]

[0599] A mixture of compound 18 (10 mg, 21.98 μmol, 1 equiv) in TFA (4.05 mmol, 1.0 mL, 30% purity, 184.3 equiv) was stirred at 35 °C for 1 h. Several new peaks were shown on LC-MS, and about 29% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 5%-35%, 8 min) to give 4B as a white solid (5.0 mg, 12.05 μmol, 54.83% yield, 100% purity). LCMS: Rt = 0.500, MS: 415.2 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 13.39 (s, 1H), 9.88 (s, 1H), 8.26 (s, 1H), 7.62 (s, 1H), 5.55 (d, J = 4.4 Hz, 1H), 5.17 (t, J = 7.2 Hz, 1H), 5.02 (s, 1H), 5.00 (t, J = 8.4 Hz, 1H), 4.34 (s, 3H), 4.02 - 4.00 (m, 1H), 2.06 - 2.04 (m, 1H), 1.99 - 1.96 (m, 1H), 1.55 - 1.53 (m, 1H). LCMS: Rt = 2.001, MS: 415.1 (M+H) + 。

[0600] Example 10: Synthesis of 6B

[0601] Compound 11 was prepared as in Example 7 for 3B

[0602]

[0603] General procedure for the preparation of compound 12

[0604]

[0605] To a solution of compound 11 (700 mg, 1.43 mmol, 1.0 equiv) in NMP (10 mL) was added NH3.H2O (12.1 g, 86.25 mmol, 25% purity, 60.51 equiv). The mixture was stirred at 140 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc (30 mL × 3) and water (50 mL). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give compound 12 as a yellow solid (600 mg, 1.27 mmol, 89.2% yield). LCMS: Rt = 0.806, MS: 472.0 (M+H) + . 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 8.21 (s, 1H), 6.80 (s, 2H), 5.50 (d, J = 7.2 Hz, 1H), 5.07 (s, 1H), 4.86 - 4.79 (m, 1H), 2.57 (dd, J = 5.6, 9.2 Hz, 1H), 1.64 (dd, J = 5.6, 9.2 Hz, 1H), 1.48 (s, 3H), 1.41 (t, J = 5.6 Hz, 1H), 1.19 (s, 3H).

[0606] General procedure for the preparation of compound 14

[0607]

[0608] At 25 °C, under N2, KF (783.41 mg, 13.48 mmol, 12 equiv), Et3N (2.35 mL, 16.85 mmol, 15 equiv), CuI (42.80 mg, 224.73 μmol, 0.2 equiv) and Pd(PPh3)2Cl2 (157.74 mg, 224.73 μmol, 0.2 equiv) were added to a mixture of compound 12 (530 mg, 1.12 mmol, 1.0 equiv) and compound 13 (1.26 g, 11.24 mmol, 10 equiv) in DMF (10 mL). The mixture was stirred at 60 °C for 1 h. LCMS showed the reaction was complete. The solid was removed by filtration, and the filtrate was partitioned between EtOAc (10 mL x 3) and H2O (20 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (SiO2, 50% - 100% ethyl acetate / petroleum ether) to give compound 14 (400 mg) as a yellow solid. LCMS: Rt = 0.769, MS: 384.3 (M+H) + 。 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 8.25 - 8.16 (m, 1H), 7.13 - 6.67 (m, 2H), 5.54 - 5.47 (m, 1H), 5.05 (s, 1H), 4.82 (dd, J = 1.2, 6.8 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.19 - 2.11 (m, 3H), 1.64 (dd, J = 6.0, 8.8 Hz, 1H), 1.48 (s, 3H), 1.41 (t, J = 5.6 Hz, 1H), 1.19 (s, 3H).

[0609] General procedure for the preparation of compound 15

[0610]

[0611] To a solution of compound 14 (50 mg, 130.27 μmol, 1 equiv) in DMF (1 mL) was added t-BuOK (36.5 mg, 325.7 μmol, 2.5 equiv). The mixture was stirred at 60 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (20 mL). The combined organic layers were washed with brine (15 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 15 (50 mg, crude) as a red oil, which was used directly in the next step. LCMS: Rt = 0.765, MS: 384.3 (M+H) + 。

[0612] General procedure for the preparation of Compound 16

[0613]

[0614] Dissolve Compound 15 (180 mg, 468.96 μmol, 1.0 equiv) in HCl / MeOH (10 mL) and stir at 25 °C for 16 h. TLC (ethyl acetate) shows the reaction is complete. Concentrate the mixture under reduced pressure to give Compound 16 (170 mg, crude) as a yellow solid. Use the residue directly in the next step. LCMS of the reaction mixture: Rt = 0.531, MS: 376.1 (M+H) + 。

[0615] General procedure for the preparation of Compound 18

[0616]

[0617] Dilute the crude Compound 16 (170 mg, 412.35 μmol, 1.0 equiv, HCl) with MeOH (5 mL), then add Compound 17 (0.42 mL, 2.89 mmol, 7.0 equiv) to the solution. Stir the mixture at 25 °C for 1 h. LCMS shows the reaction is complete. Use the mixture directly in the next step. LCMS: Rt = 0.619, MS: 477.4 (M+H) + 。

[0618] General procedure for the preparation of 6B

[0619]

[0620] Add HCl (1.0 mL) to the mixture from the above step and stir at 80 °C for 1 h. LCMS shows the reaction is complete. Concentrate the mixture under reduced pressure. Purify the residue by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 5% - 35%, 8 min) to give 6B (26.8 mg, 16.4% yield, 96.4% purity) as a white solid. LCMS: Rt = 2.205, MS: 384.9 (M+H) + 。 11H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.34 (s, 1H), 11.85 (s, 1H), 8.46 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 6.33 (s, 1H), 5.44 (d, J = 4.4 Hz, 1H), 5.06 - 4.96 (m, 2H), 4.79 (d, J = 8.0 Hz, 1H), 3.85 (t, J = 5.2 Hz, 1H), 2.44 - 2.41 (m, 3H), 1.87 - 1.79 (m, 2H), 1.46 (dd, J = 2.4, 5.6 Hz, 1H).

[0621] Table 1. Compounds Prepared in This Article and Determination Data

[0622]

[0623]

[0624]

[0625]

[0626] Example 11: Preparation of Compound 16A*

[0627]

[0628] General Procedure for the Preparation of Compound 2*

[0629]

[0630] To a solution of compound 1* (7 g, 45.41 mmol) in MeOH (140 mL) was added CeCl3 (11.19 g, 45.41 mmol), and then NaBH4 (1.98 g, 52 mmol) was added portionwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (500 ml), then extracted with DCM (150 mL × 3), and then the combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtration, the solvent was concentrated in vacuo. The residue was purified by chromatography (SiO2, PE / EA = 10 / 1, 5 / 1 to 3 / 1) to obtain compound 2* (4.2 g, 59% yield) as a colorless oil. 1 1H NMR: 400 MHz, chloroform-d, δ (ppm): 5.87 (s, 2H), 5.00 (d, J = 6.0 Hz, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H), 2.62 (s, 1H), 1.42 (s, 3H), 1.39 (s, 3H)

[0631] General procedure for the preparation of compound 3*

[0632]

[0633] At 0 °C, Et2Zn (1 M, 112.7 mL) was added to a solution of compound 2* (4.4 g, 28 mmol) in DCM (500 mL). The mixture was stirred at 0 °C for 15 min, then CH2I2 (225.38 mmol, 18.2 mL) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NH4Cl solution (500 mL) and H2O (1000 mL), and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was purified by chromatography (SiO2, PE / EA = 20 / 1 to 5 / 1) to afford compound 3* (3.49 g, 72.7% yield) as a colorless oil. 1 1H NMR: 400 MHz, CDCl3-d δ (ppm) 4.89 (t, J = 6.4 Hz, 1H), 4.55 - 4.47 (m, 2H), 2.21 (s, 1H), 1.86 - 1.84 (m, 1H), 1.66 - 1.65 (m, 1H), 1.56 (s, 3H), 1.30 (s, 3H), 0.99 - 0.95 (m, 1H), 0.65 - 0.64 (m, 1H) General procedure for the preparation of compound 5*

[0634]

[0635] At 0 °C, PPh3 (3.12 g, 11.9 mmol) and DIAD (2.32 mL, 11.91 mmol) were added to a solution of compound 3* (1.5 g, 8.81 mmol) and compound 4* (1.49 g, 7.92 mmol) in THF (25 mL). The mixture was stirred at 25 °C for 12 h, then the mixture was quenched by adding H2O (80 mL), and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was purified by chromatography (SiO2, PE / EA = 5 / 1 to 2 / 1) to afford compound 5* (0.80 g, 29% yield) as a yellow solid. LCMS of the reaction mixture: Rt = 0.721, MS: 340.0 (M+H) + 11H NMR: 400 MHz δ (ppm) 8.69 (s, 1H), 7.66 (s, 1H), 5.29 - 5.26 (m, 1H), 5.03 (s, 1H), 4.69 (d, J = 6.8 Hz, 1H), 2.01 - 1.99 (m, 1H), 1.81 - 1.79 (m, 1H), 1.44 (s, 3H), 1.16 (s, 3H), 0.87 - 0.80 (m, 2H)

[0636] General procedure for the preparation of compound 6*

[0637]

[0638] At -70 °C, under N2, 1 M LiHMDS (13.23 mL) was added dropwise to a solution of compound 5* (1.8 g, 5.29 mmol), TIPSCl (1.70 mL, 7.94 mmol), and HMPA (9.30 mL, 52.9 mmol) in THF (20 mL). The mixture was stirred at -70 °C for 3 h, then quenched by the addition of saturated aqueous NH4Cl solution (40 mL) and then extracted with EA (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated and then purified by chromatography (SiO2, PE) to give compound 6* as a white solid (2 g, 76% yield). LCMS of the reaction mixture: MS: 496.1 (M + H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 7.61 (s, 1H), 5.45 - 5.40 (m, 1H), 4.89 (d, J = 7.2 Hz, 1H), 4.72 (s, 1H), 1.98 - 1.94 (m, 1H), 1.64 - 1.50 (m, 4H), 1.20 - 1.11 (m, 24H), 0.89 - 0.81 (m, 1H), 0.71 - 0.69 (m, 1H).

[0639] General procedure for the preparation of compound 7*

[0640]

[0641] At -70 °C, 2 M LDA (403 μL) was added to a solution of compound 6* (200 mg, 402 μmol) in THF (4 mL) under N₂. The mixture was stirred at -70 °C for 0.5 h, and then a solution of compound 12* (218.7 mg, 1.01 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h. The mixture was quenched at 20 °C by adding saturated aqueous NH₄Cl solution (15 mL) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, concentrated and then purified by preparative TLC (PE / EA = 5:1) to give compound 7* as a white solid (205 mg, 71% yield). LCMS of the reaction mixture: MS: 713.2 (M+H) + 。 1 ¹H NMR: 400 MHz DMSO-d₆ δ (ppm) 7.85 - 7.74 (m, 4H), 5.57 - 5.49 (m, 1H), 5.48 - 5.20 (m, 2H), 4.87 - 4.72 (m, 1H), 4.72 - 4.62 (m, 1H), 4.61 - 4.33 (m, 1H), 2.85 - 2.82 (m, 1H), 2.29 - 2.16 (m, 1H), 2.00 - 1.85 (m, 1H), 1.62 - 1.47 (m, 4H), 1.43 - 1.41 (m, 6H), 1.23 - 1.04 (m, 21H), 0.89 - 0.77 (m, 1H), 0.71 - 0.68 (m, 1H)

[0642] General procedure for the preparation of compound 8*

[0643]

[0644] At 25 °C, NH₂NH₂·H₂O (71.9 μL, 1.26 mmol, 85% purity) was added to a solution of compound 7* (180 mg, 251 μmol) in EtOH (4 mL). The mixture was stirred at 60 °C for 2 h and then concentrated under reduced pressure to give crude compound 8* as a yellow oil, which was used directly in the next step. LCMS of the reaction mixture: MS: 583.2 (M+H) + 。General procedure for the preparation of compound 9*

[0645]

[0646] To a solution of compound 8* (150 mg, 257 μmol) in NMP (10 mL) was added DIPEA (0.22 mL, 1.28 mmol), and the mixture was stirred at 100 °C for 16 h. The mixture was partitioned between EA (10 mL × 3) and water. The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, concentrated and then purified by preparative TLC (PE / EA = 20:1) to afford compound 9* as a white solid (35 mg, 34% yield). LCMS of the reaction mixture: MS: 391.1 (M+H) + 。

[0647] General procedure for the preparation of compound 16A*

[0648]

[0649] To a solution of compound 9* (35 mg, 89.55 μmol) in DCM (1 mL) was added Et3SiH (0.5 mL) and TFA (0.5 mL). The mixture was stirred at 25 °C for 3 h, then concentrated and purified by preparative HPLC (column: Waters Xbridge BEHC18 100×30 mm×10um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to afford compound 16A* as a white solid (9.91 mg, 33% yield). LCMS of the reaction mixture: MS: 335.0 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 8.09 (s, 1H), 7.21 (s, 1H), 5.09 (dd, J = 2.8, 4.4 Hz, 1H), 4.67 (s, 1H), 4.61 - 4.59 (m, 1H), 4.52 (d, J = 7.2 Hz, 1H), 3.78 - 3.69 (m, 1H), 3.56 - 3.46 (m, 1H), 2.80 - 2.67 (m, 2H), 2.02 - 1.89 (m, 1H), 1.81 - 1.79 (m, 1H), 1.56 (br dd, J = 4.8, 8.8 Hz, 1H), 1.46 (dd, J = 4.4, 8.8 Hz, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.11 - 1.10 (m, 1H), 0.61 - 0.59 (m, 1H).

[0650] General procedure for the preparation of compound 12-3*

[0651]

[0652] Compound 12-1* (5 g, 56 mmol) and compound 12-2* (9.14 g, 61.7 mmol) in toluene (150 mL) were stirred at 110 °C for 3 h. The mixture was concentrated and purified by chromatography (SiO2, 20%-30% EA / PE) to give compound 12-3* (5.1 g, 41% yield) as a white solid. LCMS of the reaction mixture: MS: 220.1 (M+H) + 1 1H NMR: 400 MHz CDCl3 δ (ppm) 7.84 - 7.79 (m, 2H), 7.74 - 7.68 (m, 2H), 4.63 - 4.54 (m, 1H), 3.69 - 3.62 (m, 1H), 3.59 - 3.51 (m, 1H), 2.28 - 2.23 (m, 1H), 2.00 - 1.86 (m, 1H), 1.55 (d, J = 7.2 Hz, 3H).

[0653] General procedure for the preparation of compound 12*

[0654]

[0655] A solution of compound 12-3* (1.0 g, 4.56 mmol) in DCM (5 mL) was rapidly added to a suspension of PCC (1.47 g, 6.84 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 3 h. The solid was filtered off and the filtrate was concentrated and purified by chromatography (SiO2, 25%-30% EA / PEr) to give compound 12* (620 mg, 62% yield) as a white solid. LCMS of the reaction mixture: MS: 218.1 (M+H) + 1 1H NMR: 400 MHz CDCl3 δ (ppm) 9.76 (s, 1H), 7.86 - 7.80 (m, 2H), 7.75 - 7.69 (m, 2H), 4.99 - 4.86 (m, 1H), 3.35 - 3.28 (m, 1H), 3.05 - 2.99 (m, 1H), 1.51 (d, J = 7.2 Hz, 3H)

[0656] Example 12: Preparation of Compound 15A*

[0657]

[0658]

[0659] Compound 6* was prepared as in Example 11

[0660] General procedure for the preparation of compound 8*

[0661]

[0662] At -70 °C, 2M LDA (1.31 mL) was added to a solution of compound 6* (650 mg, 1.31 equiv) in THF (10 mL) under N2. The mixture was stirred at -70 °C for 0.5 h, and then a solution of compound 7* (665 mg, 3.27 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h. The mixture was quenched at 20 °C by the addition of saturated NH4Cl solution (20 mL) and then extracted with EA (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and then purified by chromatography (SiO2, 10%-20% EA / PE) to give compound 8* (460 mg, 50% yield) as a white solid. LCMS of the reaction mixture: MS: 699.1 (M+H) + 。 1 H NMR: 400 MHz CDCl3 δ (ppm) 7.89 (dt, J = 3.0, 5.5 Hz, 1H), 7.81 - 7.70 (m, 3H), 7.70 - 7.64 (m, 1H), 6.20 - 5.95 (m, 1H), 5.66 - 5.52 (m, 1H), 5.39 - 5.26 (m, 1H), 4.87 - 4.72 (m, 2H), 3.36 - 3.13 (m, 1H), 2.20 - 2.05 (m, 1H), 1.65 - 1.41 (m, 10H), 1.28 - 1.11 (m, 21H), 0.89 - 0.81 (m, 1H).

[0663] General procedure for the preparation of compound 9*

[0664]

[0665] At 25 °C, NH2NH2·H2O (81.71 μL, 1.43 mmol, 85% purity) was added to a solution of compound 8* (200 mg, 285 μmol) in EtOH (3 mL). The mixture was then stirred at 60 °C for 2 h. The mixture was cooled to 0 °C and the white solid was removed. The filtrate was concentrated under reduced pressure to give crude compound 9* (150 mg) as a yellow solid. LCMS of the reaction mixture: MS: 569.3 (M+H) + 。 11H NMR: 400 MHz CDCl3 δ (ppm) 5.69 - 5.56 (m, 1H), 5.22 - 5.09 (m, 1H), 4.95 - 4.71 (m, 2H), 3.84 - 3.65 (m, 1H), 2.16 - 2.09 (m, 1H), 1.66 - 1.59 (m, 3H), 1.56 - 1.52 (m, 3H), 1.52 - 1.46 (m, 1H), 1.44 - 1.39 (m, 2H), 1.23 - 1.20 (m, 21H), 1.08 - 1.03 (m, 1H), 0.94 - 0.80 (m, 2H)

[0666] General procedure for the preparation of compound 10*

[0667]

[0668] To a solution of compound 9* (180 mg, 316 μmol) in NMP (5 mL) was added DIPEA (275.2 μL, 1.58 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between EA (10 mL × 3) and water. The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, concentrated and then purified by preparative TLC (DCM:MeOH = 10:1) to give 10* as a yellow oil (120 mg, 254.7 μmol, 80.6% yield, 80% purity). LCMS of the reaction mixture: MS: 377.1 (M + H) + 。 1 1H NMR: 400 MHz CDCl3 δ (ppm) 7.82 (d, J = 1.9 Hz, 1H), 5.61 - 5.49 (m, 1H), 5.37 - 5.32 (m, 1H), 5.15 - 4.98 (m, 2H), 4.69 - 4.61 (m, 1H), 4.07 - 4.05 (m, 1H), 2.12 - 2.08 (m, 1H), 1.78 - 1.70 (m, 1H), 1.65 - 1.62 (m, 1H), 1.54 - 1.48 (m, 3H), 1.32 - 1.21 (m, 6H), 1.01 - 0.90 (m, 2H).

[0669] General procedure for the preparation of compound 15A*

[0670]

[0671] To a solution of compound 10* (80 mg, 212 μmol) in DCM (0.5 mL) was added Et3SiH (0.1 mL) and TFA (0.1 mL), and the mixture was then stirred at 25 °C for 3 h. The mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give compound 15A* as a white solid (22.2 mg, 32% yield). LCMS: MS: 319.0 (M+H) + 。 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 12.30 (s, 1H), 8.31 (s, 1H), 6.32 (s, 1H), 5.06 - 4.64 (m, 4H), 3.81 (d, J = 6.4 Hz, 1H), 2.42 (s, 3H), 1.88 - 1.85 (m, 1H), 1.56 - 1.54 (m, 1H), 1.17 - 1.14 (m, 1H), 0.65 - 0.63 (m, 1H).

[0672] General procedure for the preparation of compound 7-3*

[0673]

[0674] Compound 7-1* (5 g, 66.57 mmol), compound 7-2* (10.8 g, 73.2 mmol) and TEA (2.78 mL, 20.0 mmol) in toluene (150 mL) were stirred at 110 °C for 3 h. The mixture was concentrated and purified by chromatography (SiO2, 20%-30% EA / PE) to give compound 7-3* as a white solid (11.3 g, 82% yield). 1 H NMR: 400 MHz CDCl3 δ (ppm) 7.86 - 7.81 (m, 2H), 7.76 - 7.69 (m, 2H), 4.55 - 4.47 (m, 1H), 4.05 - 4.00 (m, 1H), 3.91 - 3.88 (m, 1H), 2.74 (dd, J = 4.0, 8.8 Hz, 1H), 1.45 (d, J = 7.2 Hz, 3H).

[0675] General procedure for the preparation of compound 7*

[0676]

[0677] A solution of compound 7-3* (2.0 g, 9.75 mmol) was rapidly added to a suspension of Dess-Martin reagent (6.20 g, 14.6 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 3 h, then quenched by the addition of saturated NaHCO3 and Na2S2O3 (20 mL), and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered, concentrated and then purified by chromatography (SiO2, 25%-30% EA / PE) to give compound 7* (1.7 g, 85% yield) as a white solid. 1 1H NMR: 400 MHz CDCl3 δ (ppm) 9.70 (s, 1H), 7.96 - 7.84 (m, 2H), 7.84 - 7.71 (m, 2H), 4.79 - 4.74 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H).

[0678] Example 13: Preparation of Compound 14A*

[0679]

[0680] Compound 10* was prepared as in Example 12.

[0681] General procedure for the preparation of compound 11*

[0682]

[0683] 10% Pd / C (100 mg) was added to a solution of compound 10* (100 mg, 265.37 μmol) in EtOH (10 mL) under N2. The suspension was degassed and purged with H2 three times. At 25 °C, the mixture was stirred under H2 (45 Psi.) for 7 days. LCMS showed approximately 30% desired. The solid was removed and the filtrate was concentrated under reduced pressure to give 11* (100 mg, crude) as a yellow oil, which was used directly in the next step. LCMS of the reaction mixture: Rt = 0.636, MS: 325.1 (M+H) + .

[0684] General procedure for the preparation of compound 14A*

[0685]

[0686] Compound 11* (100 mg, 308 μmol) was dissolved in TFA (10 mL) and stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 5%-45%, 8 min) to give Compound 14A* as a white solid (6.98 mg, 8% yield). LCMS: MS: 285.2 (M+H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 11.90 (s, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 6.35 (s, 1H), 5.10 (d, J = 4.4 Hz, 1H), 4.96 (s, 1H), 4.65 - 4.61 (m, 1H), 4.50 (d, J = 6.8 Hz, 1H), 3.83 - 3.80 (m, 1H), 2.41 (s, 3H), 1.88 - 1.85 (m, 1H), 1.58 - 1.56 (m, 1H), 1.17 - 1.15 (m, 1H), 0.65 - 0.63 (m, 1H).

[0687] Example 14: Preparation of Compounds 8A*, 8B*, 10A*, 11A* and 13A*

[0688]

[0689]

[0690] Compound 4* was prepared as described for Compound 12* in Example 11

[0691] General procedure for the preparation of Compound 2*

[0692]

[0693] At 20 °C, DHP (26.8 g, 319 mmol) and TsOH.Py (2.7 g, 10.6 mmol) were added to a solution of Compound 1* (20.0 g, 106 mmol) in THF (400 mL). The resulting mixture was stirred at 70 °C for 12 h, and then the mixture was concentrated under reduced pressure to give a residue. It was purified by chromatography (SiO2, PE / EA = 5:1 to 2:1) to obtain Compound 2* as a white solid (27.0 g, 93% yield). LCMS of the reaction mixture: MS: 272.0 (M+H) + 。 11H NMR: 400 MHz in DMSO-d6, δ (ppm): 8.81 (s, 1H), 7.66 (s, 1H), 5.74 - 5.71 (m, 1H), 4.07 - 3.96 (m, 1H), 3.79 - 3.65 (m, 1H), 2.32 - 2.12 (m, 1H), 2.03 - 1.93 (m, 2H), 1.83 - 1.70 (m, 1H), 1.64 - 1.56 (m, 2H). General procedure for the preparation of compound 3*

[0694]

[0695] At -70 °C under N2, 1 M LiHMDS (271.0 mL) was added dropwise to a solution of compound 2* (29.5 g, 108 mmol), TIPSCl (162 mmol, 34.8 mL), and HMPA (1.08 mol, 190.5 mL) in THF (400 mL). The mixture was stirred at -70 °C for 5 h and quenched by the addition of saturated aqueous NH4Cl solution (600 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. It was purified by chromatography (SiO2, 0% - 2% EA / PE) to afford compound 3* as a white solid (33.0 g, 71% yield). LCMS of the reaction mixture: MS: 344.1 (M - THP + H) + 。 1 1H NMR: 400 MHz in chloroform, δ (ppm): 7.24 (s, 1H), 5.45 (dd, J = 2.2, 11.1 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.63 (dt, J = 2.1, 12.0 Hz, 1H), 3.41 - 3.26 (m, 1H), 2.20 - 2.09 (m, 1H), 1.98 - 1.76 (m, 2H), 1.71 - 1.54 (m, 5H), 1.20 (dd, J = 1.4, 7.6 Hz, 18H). General procedure for the preparation of compound 5*

[0696]

[0697] At -70 °C, LDA (2 M, 9.34 mL) was added to a solution of compound 3* (4 g, 9.34 eq) in THF (80 mL) under N2. The mixture was stirred at -70 °C for 0.5 h, and compound 4* (5.07 g, 23.34 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h, then quenched at 20 °C by adding saturated aqueous NH4Cl solution (80 mL) and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and then purified by chromatography (SiO2, 5%-15% PE / EA) to give compound 5* (3.6 g, 59% yield) as a white solid. LCMS of the reaction mixture: MS: 561.1 (M-THP+H) + 。 1 1H NMR: 400 MHz CDCl3 δ (ppm) 7.83 (dd, J = 2.8, 5.6 Hz, 2H), 7.72 - 7.69 (m, 2H), 5.65 - 5.33 (m, 2H), 4.96 - 4.63 (m, 1H), 4.22 - 4.15 (m, 1H), 3.66 - 3.56 (m, 1H), 3.35 - 3.23 (m, 1H), 3.08 - 2.80 (m, 2H), 2.67 - 2.28 (m, 1H), 2.19 - 2.09 (m, 1H), 1.96 - 1.72 (m, 2H), 1.69 - 1.63 (m, 3H), 1.56 (td, J = 3.2, 6.8 Hz, 5H), 1.24 - 1.12 (m, 18H).

[0698] General procedure for the preparation of compound 6*

[0699]

[0700] At 25 °C, NH2NH2·H2O (1.59 mL, 27.8 mmol, 85% purity) was added to a solution of compound 5* (3.6 g, 5.58 mmol, 1.0 eq) in EtOH (40 mL), and then the mixture was stirred at 60 °C for 1 h. The mixture was cooled to 0 °C, the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give compound 6* (3.1 g, crude) as a yellow oil. LCMS of the reaction mixture: MS: 431.1 (M-THP+H) + 。

[0701] General procedure for the preparation of compound 7*

[0702]

[0703] At 25 °C, DIPEA (4.73 mL, 27.1 mmol) was added to a solution of compound 6* (2.8 g, 5.43 mmol) in NMP (30 mL). The mixture was then stirred at 100 °C for 12 h. The mixture was partitioned between EA (20 mL × 3) and water (20 mL). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, concentrated and then purified by chromatography (SiO2, 30%-70% EA / PE) to give compound 7* as a yellow oil (1.9 g, 68% yield, 63% purity). LCMS of the reaction mixture: MS: 323.1 (M+H) + 。 1 H NMR: 400 MHz CDCl3 δ (ppm) 7.95 (s, 1H), 5.77 (s, 1H), 5.73 - 5.69 (m, 1H), 5.10 (t, J = 2.8 Hz, 1H), 4.17 - 4.08 (m, 1H), 2.20 - 2.12 (m, 2H), 2.11 - 1.92 (m, 7H), 1.78 - 1.65 (m, 2H), 1.46 - 1.33 (m, 3H). General procedure for the preparation of compound 8*

[0704]

[0705] IBX (1.35 g, 4.83 mmol) was added portionwise to a solution of compound 7* (1.2 g, 3.72 mmol) in ACN (15 mL). The mixture was stirred at 80 °C for 2 h, then the mixture was cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure to give compound 8* as a yellow oil (1.2 g, crude). LCMS of the reaction mixture: MS: 237.0 (M-THP+H) + 。

[0706] General procedure for the preparation of compound 9*

[0707]

[0708] Under N2, NH4OAc (418.47 mg, 5.43 mmol) was added to a solution of compound 9* (200 mg, 362 μmol) in MeOH (3 mL) and the mixture was stirred for 0.5 h. Then NaBH3CN (45.49 mg, 723 μmol) was added and the mixture was heated to 65 °C and stirred for 4 h. The mixture was quenched with 1 M NaOH (10 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 10* as a yellow oil (180 mg, crude). LCMS of the reaction mixture: MS: 237.1 (M+H) + 。 1 H NMR: 400 MHz CDCl3 δ (ppm) 13.29 - 12.71 (m, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 3.94 - 3.83 (m, 1H), 2.73 - 2.64 (m, 1H), 2.53 (s, 1H), 1.28 (d, J = 6.4 Hz, 3H).

[0709] General procedure for the preparation of compound 10*

[0710]

[0711] At 25 °C, under N2, PPh3 (820.1 mg, 3.13 mmol) and DIAD (608 μL, 3.13 mmol) were added to a solution of compound 9* (370 mg, 1.56 mmol) and compound Int.10* (1.04 g, 2.35 mmol) in THF (15 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was concentrated and purified by chromatography (SiO2, 50% - 80% EA / PE) to give compound 10* as a yellow gum (1.1 g, 85% yield, 80% purity). LCMS of the reaction mixture: MS: 661.3 (M+H) + 。 11H NMR: 400 MHz DMSO-d6 δ (ppm) 8.45 (s, 1H), 8.32 (d, J = 3.6 Hz, 1H), 7.48 - 7.06 (m, 15H), 5.31 (d, J = 7.2 Hz, 1H), 4.93 (s, 1H), 4.73 (dd, J = 2.8, 6.4 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.44 - 3.35 (m, 1H), 3.27 - 3.19 (m, 1H), 2.77 - 2.64 (m, 1H), 2.46 (d, J = 8.8 Hz, 1H), 1.68 - 1.52 (m, 1H), 1.46 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.21 - 1.17 (m, 3H), 1.00 (t, J = 4.8 Hz, 1H), 0.88 (dd, J = 5.2, 9.2 Hz, 1H).

[0712] General procedure for the preparation of Compound 11* and Compound 13A*

[0713]

[0714] At 30 °C, AcOH (1.52 mL, 21.31 mmol; 80% aqueous solution) was added to a solution of Compound 10* (300 mg, 226.8 μmol, 50% purity) in ACN (1 mL). The mixture was stirred at 30 °C for 16 h, then the mixture was basified to pH 8 with NH3·H2O and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS of the reaction mixture: 0.657, MS: 379.1 (M + H) + , 419.1 (M + H) + . The residue was purified by chromatography (SiO2, PE / EA = 5:1 to 1:3) to give Compound 11* as a yellow solid (60 mg, 63.1% yield). 11H NMR: 400 MHz in CDCl3, δ (ppm): 7.85 (s, 1H), 6.71 (s, 1H), 5.59 (d, J = 7.6 Hz, 1H), 4.77 (s, 1H), 4.71 (dd, J = 0.8, 7.6 Hz, 1H), 4.23 (d, J = 11.6 Hz, 1H), 4.08 - 3.97 (m, 1H), 3.41 (d, J = 11.6 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.67 - 2.63 (m, 1H), 2.12 (s, 1H), 1.71 - 1.69 (m, 1H), 1.55 (s, 3H), 1.47 - 1.42 (m, 3H), 1.26 (s, 3H), 1.15 (t, J = 5.2 Hz, 1H), 1.00 - 0.98 (m, 1H). The crude compound 13 was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 10% - 40%, 8 min) to give pure 13A* as a white solid (15.63 mg, 18.1% yield, 99.6% purity). 1 1H NMR: 400 MHz in DMSO - d6, δ (ppm): 8.48 (s, 1H), 8.37 (s, 1H), 5.23 (d, J = 3.2 Hz, 1H), 5.00 (t, J = 3.2 Hz, 1H), 4.72 (s, 1H), 4.57 - 4.55 (m, 1H), 4.49 - 4.47 (m, 1H), 4.09 - 4.05 (m, 1H), 3.95 - 3.80 (m, 1H), 3.69 - 3.67 (m, 1H), 3.17 - 3.14 (m, 1H), 2.75 - 2.65 (m, 1H), 2.48 - 2.46 (m, 1H), 1.45 - 1.43 (m, 1H), 1.34 (t, J = 4.4 Hz, 1H), 1.26 (d, J = 6.4 Hz, 3H), 0.63 - 0.60 (m, 1H). LCMS of compound 13A*: MS: 379.1 (M + H) + 。

[0715] General procedure for the preparation of compound 12*

[0716]

[0717] At 20 °C, IBX (156 mg, 558 μmol) was added to a solution of compound 11* (180 mg, 429 μmol) in ACN (3 mL). The mixture was stirred at 80 °C for 1 h. The solid was removed by filtration and the filtrate was used directly in the next step.

[0718] General procedure for the preparation of compound 13*

[0719]

[0720] At 20 °C, NaH2PO4 (103.6 mg, 863.6 μmol) in H2O (1.1 mL) and 30% aqueous H2O2 solution (41.5 μL, 431.80 μmol) were added to a solution of compound 12* (180 mg, 431.8 μmol) in ACN (8 mL). A solution of sodium chlorite (58.5 mg, 518.1 μmol, 80% purity) in H2O (1.3 mL) was added thereto at 0 °C. The mixture was stirred at 20 °C for 1 h, then quenched at 0 °C by adding saturated aqueous Na2S2O3 solution (20 mL) and extracted with EA (10 mL × 10). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 13* (200 mg, crude) as a white solid. LCMS of compound 13A*: MS: 431.1 (M-H) - 。

[0721] General procedure for the preparation of compound 14*

[0722]

[0723] At 0 °C, DIPEA (126.7 μL, 727.7 μmol) and T3P (144 μL, 242.57 μmol, 50%, in EA) were added to a solution of compound 13* (70 mg, 161.7 μmol), MeNH2·HCl (10.92 mg, 161.72 μmol) in THF (2 mL). The mixture was stirred at 25 °C for 1 h, then partitioned between EA (50 mL × 2) and water 20 mL. The organic phase was separated, washed with saturated NaCl (50 mL), dried over Na2SO4, filtered, concentrated and then purified by preparative TLC (EA) to give compound 14* (10 mg, 14% yield) as a pale yellow solid. LCMS of the reaction mixture: MS: 446.2 (M+H) + 。 11H NMR: 400 MHz DMSO-d6 δ (ppm) 8.44 (s, 1H), 8.18 (s, 1H), 7.75 - 7.67 (m, 1H), 5.63 (d, J = 7.2 Hz, 1H), 4.95 (s, 1H), 4.81 - 4.68 (m, 1H), 3.96 - 3.81 (m, 1H), 2.75 - 2.66 (m, 2H), 2.63 (d, J = 4.4 Hz, 3H), 2.10 - 2.02 (m, 1H), 1.49 - 1.41 (m, 4H), 1.28 - 1.18 (m, 7H).

[0724] General procedure for the preparation of compound 10A*

[0725]

[0726] Dissolve compound 14* (150 mg, 336 μmol) in TFA (0.5 mL) and Et3SiH (0.5 mL). Stir the mixture at 25 °C for 16 h, then concentrate the mixture under reduced pressure. Purify the residue by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; B%: 10% - 40%, 8 min) to give compound 10A* as a white solid (36.28 mg, 27% yield, 100% purity). LCMS: MS: 392.1 (M + H) + 。 1 1H NMR: 400 MHz DMSO-d6 δ (ppm) 7.98 (s, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.24 (s, 1H), 5.38 (d, J = 3.2 Hz, 1H), 4.97 - 4.94 (m, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.69 (s, 1H), 3.86 - 3.82 (m, 1H), 3.49 (s, 1H), 2.77 - 2.67 (m, 5H), 1.77 - 1.61 (m, 1H), 1.60 - 1.59 (m, 1H), 1.45 - 1.58 (m, 2H), 1.30 - 1.21 (m, 4H).

[0727] General procedure for the preparation of compound 11A*

[0728]

[0729] Compound 14* (50 mg, 112 μmol) was dissolved in TFA (3 mL, 30% purity). The mixture was stirred at 25 °C for 1 h, then the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 1%-35%, 8 min) to give Compound 11A* as a white solid (18.24 mg, 40.0% yield, 100% purity). LCMS: MS: 321.1 (M+H) + . 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 8.42 (s, 1H), 8.14 (s, 1H), 7.57 - 7.55 (m, 1H), 5.44 - 5.43 (m, 1H), 4.98 - 4.94 (m, 1H), 4.86 - 4.84 (m, 1H), 4.71 (s, 1H), 3.88 (t, J = 5.2 Hz, 2H), 2.70 - 2.66 (m, 4H), 2.48 - 2.51 (m, 1H), 1.81 - 1.79 (m, 1H), 1.60 (t, J = 4.8 Hz, 1H), 1.31 - 1.25 (m, 4H). General procedure for the preparation of Compound 15*

[0730]

[0731] To a solution of Compound 14* (45 mg, 100 μmol) in EtOH (1 mL) was added NaBH4 (11.45 mg, 302 μmol), and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with H2O (10 mL) and then extracted with EA (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give Compound 15* as a yellow solid (40 mg, crude). LCMS: 0.627, MS: 448.2 (M+H) + .

[0732] General procedure for the preparation of Compound 8A* and Compound 8B*

[0733]

[0734] Compound 15* (40 mg, 89.3 μmol) was dissolved in TFA (3 mL, 30% purity). The mixture was stirred at 25 °C for 1 h, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 1%-30%, 8 min) to give Compound 8A* as a white solid (4.53 mg, 10% yield, 83% purity) LCMS: MS: 408.2 (M+H) + . 1 H NMR: 400 MHz DMSO-d6 δ (ppm) 8.01 (s, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.42 (s, 1H), 5.40 (...

Claims

1. A compound represented by formula (I*): or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a C5-C6 carbocyclic ring and a 5- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from R 51 ; R 51 selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group, -C(O)R 30 , -C(O)OR 30 ; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ; R 1 selected from O, S, and C(R 21 )2; Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded forms a 3-membered carbon ring and the other R 21 is hydrogen; When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen; R 52 selected from hydrogen, -NO2, -CN, -NH2, halogen and L 2 -Y 2 ; L 2 selected from a bond, O, NH, and S; Y 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C 3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, the C 3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 aminoalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring; R 55 selected from hydrogen, -CN, C1-C6 haloalkyl, C1-C6 alkyl, -C(O)N(H)(R 11 ) and -CH2OR 12 ; R 59 selected from hydrogen, -OH, -NH2 and F; R 11 selected from hydrogen and C1-C6 alkyls and C3-C5 cycloalkyls; R 12 selected from hydrogen, C1-C6 alkyl, and -C(O)C1-C 10 alkyl; Each R 30 , R 31 , R 32 and R 33 is independently selected, at each occurrence, from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ; R 34 selected from C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, wherein the C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy; and R 35 Each independently at each occurrence is selected from C optionally substituted by one or more substituents independently selected from the following 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy group.

2. The compound or salt according to claim 1, wherein R 1 is selected from O and C(R 21 )2.

3. The compound or salt according to claim 1, wherein R 1 is selected from C(R 21 )2.

4. The compound or salt according to claim 1 or 2, wherein R 1 is C(R 21 )2, and R 22 and one R 21 together with the atoms to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen.

5. The compound or salt according to claim 1, wherein R 1 is O and R 22 is hydrogen.

6. The compound or salt according to any one of claims 1 to 5, wherein ring A is selected from optionally substituted 5- to 6-membered heterocycles.

7. The compound or salt according to any one of claims 1 to 6, wherein ring A is selected from optionally substituted 5- to 6-membered heterocycles, wherein the heterocycle contains 1 to 2 nitrogen atoms.

8. The compound or salt according to any one of claims 1 to 6, wherein ring A is selected from optionally substituted 5- to 6-membered heterocycles, wherein the heterocycle contains 1 nitrogen atom.

9. The compound or salt according to any one of claims 1 to 8, wherein ring A is selected from Each of which is optionally substituted by one or more substituents independently selected from R 51 substituents.

10. The compound or salt according to any one of claims 1 to 8, wherein ring A is selected from optionally substituted 5-membered heterocycles, wherein the heterocycle contains 1 to 2 nitrogen atoms.

11. The compound or salt according to claim 10, wherein ring A is selected from each of which is optionally substituted by one or more substituents independently selected from R 51 substituents.

12. The compound or salt according to any one of claims 1 to 11, wherein R 51 is selected from optionally substituted C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, oxo group, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

13. The compound or salt according to any one of claims 1 to 12, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being substituted by one or more substituents independently selected from optionally substituted C 3-6 carbocycles, wherein C 3-6 the carbocycle is optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

14. The compound or salt according to claim 10 or 11, wherein R 33 is selected from C 1-6 alkyl substituted by one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 .

15. The compound or salt according to any one of claims 10 to 12, wherein R 33 is selected from C 1-6 alkyl substituted with a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

16. The compound or salt according to any one of claims 1 to 9, wherein each R 51 is independently selected from -OH, =O, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from halogen, =O, phenyl, and wherein the phenyl is optionally substituted by one or more substituents independently selected from halogen.

17. The compound or salt according to any one of claims 1 to 9 or 14, wherein each R 51 is independently selected from -CH3, -OH and =O.

18. The compound or salt according to any one of claims 1 to 11, wherein each R 51 is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from halogen, =O, phenyl, wherein the phenyl is optionally substituted by one or more substituents independently selected from halogen.

19. The compound or salt according to any one of claims 1 to 11 or 15, wherein each R 51 is selected from -CH3, 20. The compound or salt according to any one of claims 1 to 11, wherein each R 51 is independently selected from C1-C6 alkyl.

21. A compound or salt according to any one of claims 1 to 11 or 20, wherein each R 51 is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more substituents independently selected from halogen, =O, phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen.

22. The compound or salt according to claim 1, wherein ring A is selected from 23. The compound or salt according to any one of claims 1 to 22, wherein each R 59 is the same.

24. The compound or salt according to any one of claims 1 to 22, wherein R 59 is selected from -OH and -NH2.

25. The compound or salt according to any one of claims 1 to 22, wherein R 59 is -OH.

26. The compound or salt according to any one of claims 1 to 25, wherein formula (I*) is represented by formula (II-A*) or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from O and C(R 21 )2.

27. The compound or salt according to any one of claims 1 to 25, wherein formula (I*) is represented by formula (II*) or a pharmaceutically acceptable salt thereof: wherein X is selected from NH, O, and S.

28. The compound or salt according to any one of claims 1 or 27, wherein formula (I*) is represented by formula (II-B*) or a pharmaceutically acceptable salt thereof:

29. The compound or salt according to any one of claims 1 to 22, wherein each R 59 is different.

30. The compound or salt according to any one of claims 1 to 25 or 29, wherein formula (I*) is represented by formula (III*) or a pharmaceutically acceptable salt thereof: X is selected from CH2 and NH; m is selected from 1 and 2; and n is selected from 0, 1, 2; and when m is 2, n is further selected from n is 3.

31. The compound or salt according to any one of claims 1 to 25 or 29, wherein formula (I*) is represented by formula (IV*) or a pharmaceutically acceptable salt thereof: wherein X is NH; m is selected from 1 and 2; and n is selected from 0, 1, and 2; and when m is 2, n is further selected from n is 3.

32. The compound or salt according to any one of claims 1 to 31, wherein R 55 is selected from hydrogen, -C(O)N(H)(R 11 ) and -CH2OR 12 .

33. The compound or salt according to claim 32, wherein R 12 is hydrogen.

34. The compound or salt according to claim 32, wherein R 55 is selected from hydrogen and -C(O)N(H)(R 11 ).

35. The compound or salt according to claim 34, wherein R 11 is selected from hydrogen and C1-C3 alkyl.

36. The compound or salt according to claim 35, wherein R 11 is selected from C1-C3 alkyl.

37. The compound or salt according to claim 34, wherein R 55 is selected from hydrogen.

38. The compound or salt according to any one of claims 1 to 32, wherein R 55 is -C(O)N(H)(Me).

39. The compound or salt according to any one of claims 1 to 32, wherein R 55 is -CH2OH.

40. The compound or salt according to any one of claims 1 to 39, wherein R 52 is selected from hydrogen, halogen and L 2 -Y 2 wherein L 2 is a bond and Y 2 is C2-C6 alkynyl optionally substituted by one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy.

41. The compound or salt according to claim 40, wherein Y 2 is a C2-C6 alkynyl group substituted with an unsubstituted C 3-6 carbocyclic ring.

42. The compound or salt according to claim 41, wherein R 52 is 43. The compound or salt according to any one of claims 1 to 39, wherein R 52 is L 2 -Y 2 wherein L 2 is -O- and Y 2 is selected from C1-C6 alkyl.

44. The compound or salt according to claim 43, wherein R 52 is -O-CH2-CH3.

45. The compound or salt according to any one of claims 1 to 39, wherein R 52 is selected from hydrogen and halogen.

46. The compound or salt according to claim 45, wherein R 52 is a halogen.

47. The compound or salt according to claim 45, wherein R 52 is chlorine.

48. The compound or salt according to claim 45, wherein R 52 is hydrogen.

49. The compound or salt according to any one of claims 1 to 39, wherein R 52 is -CN.

50. The compound or salt according to any one of claims 1 to 39, wherein R 52 is -NH2.

51. A compound or salt according to any one of claims 1 to 39, wherein R 52 is selected from halogen, -CN, -NH2 and L 2 -Y 2 ; wherein L 2 is selected from O and a bond, where L 2 is selected from O, Y 2 is selected from C1-C6 alkyl, and wherein when L 2 is a bond, Y 2 is selected from C2-C6 alkynyl, and the C2-C6 alkynyl is substituted by C 3-6 carbocyclic ring.

52. A compound or salt according to any one of claims 1 to 39 or 51, wherein R 52 is selected from -Cl, -CN, -NH2, 53. The compound or salt according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt of any of them.

54. The compound or salt according to claim 1, wherein the compound is selected from: and salts thereof.

55. A compound represented by formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from O, S, and C(R 21 )2; R 51 selected from -OR 30 , optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, each optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)N(R 31 )2, -N(R 31 )C(O)OR 31 , -C(O)R 31 , C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ; L is selected from N and C(R 12 )); R 12 selected from hydrogen, halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl, wherein the alkyl moiety of the -O-C 1-6 alkyl and the C 1-6 alkyl are each optionally substituted by one or more substituents selected from: halogen, -OH, -NH2, -NO2, -CN, -O-C 1-6 alkyl, C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring; wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from: halogen, hydroxy, -NO2, -CN, -NH2, -O-C 1-6 alkyl and C 1-6 alkyl; When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen; Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen; R 52 selected from hydrogen, -NO2, -CN, -NH2, halogen and L 2 -Y 2 ; L 2 Selected from a bond, O, NH, and S; Y 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C 3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, the C 3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 aminoalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring; R 55 Selected from optionally substituted 3- to 6-membered heterocycles, wherein the 3- to 6-membered heterocycles are optionally substituted with one or more substituents independently selected from the following: halogen, -OR 33 , -SR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )C(O)R 33 , -N(R 33 )C(O)N(R 33 )2, -N(R 33 )C(O)OR 33 , -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl; R 59 selected from hydrogen, -OH, -NH2, and F; and Each R 30 、R 31 、R 32 and R 33 is independently selected, at each occurrence, from hydrogen and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, where the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ; R 34 selected from C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, wherein the C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and R 35 Each, independently at each occurrence, is selected from C optionally substituted with one or more substituents independently selected from the following 1-6 alkyl groups: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycles and 3- to 6-membered heterocycles, where the C 3-6 carbocycles and 3- to 6-membered heterocycles are each optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

56. The compound or salt according to claim 55, which is represented by formula (II) or a pharmaceutically acceptable salt thereof:

57. The compound or salt according to claim 55 or 56, wherein for R 55 , the 3- to 6-membered heterocycle has at least 1 nitrogen atom.

58. The compound or salt according to any one of claims 55 to 57, wherein R 55 is an optionally substituted 5- or 6-membered heterocycle.

59. The compound or salt according to claim 58, wherein for R 55 , the 5- to 6-membered heterocycle has at least 2 nitrogen atoms.

60. The compound or salt according to claim 59, wherein for R 55 , the 5- to 6-membered heterocycle has at least 3 nitrogen atoms.

61. The compound or salt according to any one of claims 55 to 60, wherein R 55 is an optionally substituted 5-membered heterocycle.

62. The compound or salt according to any one of claims 55 to 61, wherein R 55 is an unsubstituted 5-membered heterocycle.

63. The compound or salt according to any one of claims 55 to 61, wherein R 55 is a substituted 5-membered heterocycle.

64. A compound or salt according to any one of claims 55 to 63, wherein R 55 is selected from each of which is optionally substituted.

65. A compound or salt according to any one of claims 55 to 64, wherein R 55 is selected from each of which is optionally substituted.

66. The compound or salt according to claim 65, wherein the optional substituent is independently selected from one or more C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl.

67. The compound or salt according to claim 66, wherein the optional substituent is independently selected from one or more C 1-6 alkyl groups.

68. The compound or salt according to any one of claims 64 to 67, wherein R 55 is selected from 69. The compound or salt according to claim 68, wherein R 55 is selected from 70. The compound or salt according to claim 69, wherein R 55 is selected from 71. The compound or salt according to claim 68, wherein R 55 is selected from 72. The compound or salt according to claim 71, wherein R 55 is selected from 73. The compound or salt according to claim 72, wherein R 55 is 74. The compound or salt according to claim 72, wherein R 55 is 75. The compound or salt according to any one of claims 55 to 74, wherein R 52 is selected from halogen and -CN.

76. The compound or salt according to claim 75, wherein R 52 is selected from halogen.

77. The compound or salt according to claim 75, wherein R 52 is -Cl.

78. The compound or salt according to claim 75, wherein R 52 is -CN.

79. The compound or salt according to any one of claims 55 to 78, wherein L is N.

80. A compound or salt according to any one of claims 55 to 78, wherein L is C(R 12 ).

81. The compound or salt according to claim 80, wherein R 12 is selected from hydrogen.

82. A compound or salt according to any one of claims 55 to 81, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

83. The compound or salt according to any one of claims 55 to 82, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by one or more substituents independently selected from halogen and C 3-6 carbocyclic ring, wherein said C 3-6 carbocyclic ring is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

84. The compound or salt according to any one of claims 55 to 83, wherein R 33 is selected from C 1-6 alkyl substituted by one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 .

85. The compound or salt according to any one of claims 55 to 84, wherein R 33 is selected from C 1-6 alkyl substituted with a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

86. A compound or salt according to any one of claims 55 to 85, wherein R 51 is selected from 87. A compound or salt according to any one of claims 55 to 82, wherein R 51 is an optionally substituted C1-C6 alkyl group.

88. The compound or salt according to claim 87, wherein R 51 is selected from C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more substituents selected from fluorine and C 3-6 carbocyclic ring, wherein the C 3-6 carbocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -N(R 31 )2, -NO2, -CN and C 1-3 alkyl.

89. The compound or salt according to claim 88, wherein R 51 is selected from C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more substituents selected from fluorine and C 3-6 carbocyclic ring, wherein the C 3-6 carbocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 31 , -N(R 31 )2, -CN and C 1-3 alkyl.

90. The compound or salt according to claim 89, wherein R 51 is selected from C1-C6 alkyl groups, said C1-C6 alkyl groups being substituted by one or more substituents selected from fluorine and C 3-6 carbocyclic rings, wherein said C 3-6 carbocyclic rings are substituted by one or more substituents independently selected from halogen.

91. The compound or salt according to claim 90, wherein R 51 is a C1-C6 alkyl group optionally substituted with fluorine and phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen.

92. The compound or salt according to any one of claims 55 to 91, wherein R 51 is selected from 93. The compound or salt according to claim 89, wherein R 51 is selected from C1-C6 alkyl.

94. A compound or salt according to any one of claims 55 to 92, wherein R 51 is 95. The compound or salt according to claim 89, wherein R 51 is selected from C1-C6 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more substituents independently selected from halogen.

96. The compound or salt according to any one of claims 55 to 95, wherein each R 59 is OH.

97. A compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a C5-C6 carbocyclic ring and a 5- to 6-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from R 51 ; R 51 selected from halogen, -OR 30 , -SR 30 , -N(R 30 )2, -NO2, -CN, oxo group; optionally substituted C1-C6 alkyl, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, each of which is optionally substituted by one or more substituents independently selected from: halogen, oxo group, -OR 31 , -SR 31 , -N(R 31 )2, -S(O)2(R 31 ), -S(O)2N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)N(R 31 )2, -N(R 31 )C(O)OR 31 , -C(O)R 31 , C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, -NO2, -CN, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 ; R 1 selected from O, S, and C(R 21 )2; Each R 21 is hydrogen, or R 22 and one R 21 together with the atom to which they are bonded forms a 3-membered carbon ring and the other R 21 is hydrogen; When R 1 is selected from O and S, R 22 is selected from hydrogen; or when R 1 is C(R 21 )2, R 22 and one R 21 together with the atom to which they are bonded form a 3-membered carbon ring and the other R 21 is hydrogen; R 52 selected from hydrogen, -NO2, -CN, -NH2, halogen and -L 2 -Y 2 ; L 2 selected from a bond, O, NH, and S; Y 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OR 32 , -N(R 32 )2, -C(O)R 32 , -C(O)OR 32 , -OC(O)R 32 , -NO2, -CN, oxo group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring, wherein the C1-C6 alkyl group, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, -S-C1-C6 alkyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 aminoalkyl group, C1-C6 alkoxy group, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring; R 55 selected from optionally substituted 3- to 6-membered heterocycles, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 33 , -SR 33 , -S(O)2(R 33 ), -S(O)2N(R 33 )2, -NR 33 S(O)2R 33 , -C(O)N(R 33 )2, -N(R 33 )C(O)R 33 , -N(R 33 )C(O)N(R 33 )2, -N(R 33 )C(O)OR 33 , -N(R 33 )2, -C(O)R 33 , -C(O)OR 33 , -OC(O)R 33 , -OC(O)N(R 33 )2, -NO2, -CN, oxo group, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl; R 59 selected from hydrogen, -OH, -NH2, and F; Each R 30 , R 31 , R 32 and R 33 is independently selected, at each occurrence, from hydrogen and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the following: halogen, OH, -CN, -NO2, -NH2, oxo, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, O-C1-C6 alkyl-R 34 and -OR 35 ; R 34 selected from C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, wherein the C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and R 35 Each independently at each occurrence is selected from C optionally substituted by one or more substituents independently selected from the following 1-6 alkyl: halogen, OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 the carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl and C1-C6 alkoxy group.

98. The compound or salt according to claim 97, which is represented by formula (I-A) or a pharmaceutically acceptable salt thereof:

99. The compound or salt according to claim 97 or 98, wherein for R 55 , the 3- to 6-membered heterocycle has at least 1 nitrogen atom.

100. The compound or salt according to any one of claims 97 to 99, wherein R 55 is an optionally substituted 5- or 6-membered heterocycle.

101. The compound or salt according to claim 100, wherein for R 55 , the 5- to 6-membered heterocycle has at least 2 nitrogen atoms.

102. The compound or salt according to claim 101, wherein for R 55 , the 5- to 6-membered heterocycle has at least 3 nitrogen atoms.

103. The compound or salt according to any one of claims 97 to 102, wherein R 55 is an optionally substituted 5-membered heterocycle.

104. The compound or salt according to any one of claims 103, wherein R 55 is an unsubstituted 5-membered heterocycle.

105. The compound or salt according to any one of claims 103, wherein R 55 is a substituted 5-membered heterocycle.

106. The compound or salt according to any one of claims 97 to 105, wherein R 55 is selected from each of which is optionally substituted.

107. The compound or salt according to claim 106, wherein the optional substituent is independently selected from one or more C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl.

108. The compound or salt according to claim 107, wherein the optional substituent is independently selected from one or more C 1-6 alkyl groups.

109. The compound or salt according to any one of claims 106 to 108, wherein R 55 is selected from 110. The compound or salt according to claim 109, wherein R 55 is selected from 111. The compound or salt according to claim 106, wherein R 55 is selected from 112. The compound or salt according to claim 111, wherein R 55 is selected from 113. The compound or salt according to claim 112, wherein R 55 is 114. The compound or salt according to claim 112, wherein R 55 is 115. The compound or salt according to claim 112, wherein R 55 is 116. The compound or salt according to any one of claims 97 to 115, wherein ring A is selected from optionally substituted 5- to 6-membered heterocycles.

117. The compound or salt according to claim 116, wherein ring A is selected from optionally substituted 5-membered heterocycles.

118. The compound or salt according to any one of claims 55 to 117, wherein ring A is selected from each of which is optionally substituted.

119. The compound or salt according to any one of claims 55 to 118, wherein ring A is selected from each of which is optionally substituted.

120. The compound or salt according to any one of claims 97 to 117, wherein it is represented by formula (I-B) or a pharmaceutically acceptable salt thereof wherein X is selected from O and NH.

121. A compound or salt according to any one of claims 97 to 120, wherein R 51 is selected from optionally substituted C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN, oxo group, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycle, wherein the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

122. The compound or salt according to claim 121, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being substituted by one or more substituents independently selected from optionally substituted C 3-6 carbocyclic rings, wherein C 3-6 carbocyclic ring is optionally substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy and -OR 33 .

123. The compound or salt according to claim 122, wherein R 33 is selected from C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, oxo group, -O-C 1-6 alkyl, C1-C6 aminoalkyl, C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O-C1-C6 alkyl-R 34 and -OR 35 .

124. The compound or salt according to claim 123, wherein R 33 is selected from C 1-6 alkyl substituted with a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

125. A compound or salt according to any one of claims 97 to 121, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -NO2, -CN and oxo groups.

126. The compound or salt according to claim 125, wherein R 51 is selected from optionally substituted C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by one or more substituents independently selected from: halogen, -OR 31 , -SR 31 , -N(R 31 )2, -NO2, -CN and oxo groups.

127. The compound or salt according to claim 126, wherein R 51 is selected from optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents independently selected from -OH and oxo groups.

128. The compound or salt according to claim 127, wherein R 51 is selected from 129. The compound or salt according to claim 127, wherein R 51 is selected from 130. A compound or salt according to any one of claims 97 to 129, wherein R 52 is selected from hydrogen, halogen and L 2 -Y 2 , wherein L 2 is a bond and Y 2 is C2-C6 alkynyl optionally substituted by one or more substituents independently selected from C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring, wherein C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy.

131. The compound or salt according to claim 130, wherein Y 2 is a C2-C6 alkynyl group substituted with an unsubstituted C 3-6 carbocyclic ring.

132. A compound or salt according to any one of claims 97 to 129, wherein R 52 is selected from hydrogen, halogen and L 2 -Y 2 , wherein L 2 is a bond and Y 2 is C2-C6 alkynyl optionally substituted by one or more substituents independently selected from C 3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings, wherein the C 3-6 carbocyclic ring and 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, -NO2, -CN, oxo group, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy.

133. The compound or salt according to claim 132, wherein Y 2 is a C2-C6 alkynyl group substituted with an unsubstituted C 3-6 carbocyclic ring.

134. The compound or salt according to claim 133, wherein R 52 is 135. A compound or salt according to any one of claims 97 to 129, wherein R 52 is L 2 -Y 2 wherein L 2 is -O- and Y 2 is selected from C1-C6 alkyl.

136. The compound or salt according to claim 135, wherein R 52 is -O-CH2-CH3. The compound or salt according to any one of claims 97 to 134, wherein R 52 is selected from hydrogen and halogen.

138. The compound or salt according to claim 137, wherein R 52 is halogen.

139. The compound or salt according to claim 138, wherein R 52 is chlorine.

140. The compound or salt according to claim 137, wherein R 52 is hydrogen.

141. A compound or salt according to any one of claims 97 to 129, wherein R 52 is -CN.

142. The compound or salt according to any one of claims 97 to 129, wherein R 52 is -NH2.

143. A compound or salt according to any one of claims 97 to 129, wherein R 52 is selected from halogen, -CN, -NH2 and L 2 -Y 2 ; wherein L 2 is selected from O and a bond, where L 2 is selected from O, Y 2 is selected from C1-C6 alkyl, and wherein when L 2 is a bond, Y 2 is selected from C2-C6 alkynyl, said C2-C6 alkynyl being substituted by C 3-6 carbocyclic ring.

144. A compound or salt according to any one of claims 97 to 129, wherein R 52 is selected from -Cl, -CN, -NH2, 145. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 131 and a pharmaceutically acceptable excipient.

146. A method of treating a disease or condition, the method comprising administering to a subject in need thereof the compound or salt according to any one of claims 1 to 145 or the pharmaceutical composition according to claim 145.

147. The method according to claim 146, wherein the disease or condition is selected from vascular inflammation, arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia, cerebral palsy, chronic hypoxia due to arteriovenous malformation and occlusive cerebral artery disease, ischemia and reperfusion injury in skeletal muscle, severe neurological disorders associated with excitotoxicity, Parkinson's disease, Huntington's disease, CNS diseases, heart diseases, kidney diseases, glaucoma, cancer, neuropathic pain, transient ischemic attack, marrow protection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis, and septic shock.

148. The method according to claim 147, wherein the disease or condition is neuropathic pain.

149. The method according to claim 146, wherein the disease or condition is selected from chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, neurodegeneration, drug-induced ototoxicity, spinocerebellar degeneration, symptoms associated with traumatic brain injury, chemotherapy-induced cognitive impairment, pain and discomfort of irritable bowel syndrome, and neuropathic pain.

150. A method for activating the A3 adenosine receptor of a subject, the method comprising administering to the subject in need thereof suffering from a disease or condition the compound or salt according to any one of claims 1 to 145 or the pharmaceutical composition according to claim 146.

151. The method according to claim 150, wherein the disease or condition is selected from vascular inflammation, arthritis, allergy, asthma, wound healing, stroke, heart failure, acute spinal cord injury, acute head injury or trauma, seizure, neonatal hypoxia, cerebral palsy, chronic hypoxia attributable to arteriovenous malformation and occlusive cerebral arterial disease, ischemia and reperfusion injury in skeletal muscle, severe neurological disorders associated with excitotoxicity, Parkinson's disease, Huntington's disease, CNS diseases, heart diseases, kidney diseases, glaucoma, cancer, neuropathic pain, transient ischemic attack, bone marrow protection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis, and septic shock.

152. The method according to claim 151, wherein the disease or condition is neuropathic pain.

153. The method according to claim 150, wherein the disease or condition is selected from chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, neurodegeneration, drug-induced ototoxicity, spinocerebellar degeneration, symptoms associated with traumatic brain injury, chemotherapy-induced cognitive impairment, pain and discomfort of irritable bowel syndrome, and neuropathic pain.

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